tag:blogger.com,1999:blog-47910852492317907092024-03-17T23:03:25.629-04:00Treating AchondroplasiaUm blog dedicado ao tratamento da acondroplasia.
A blog dedicated to the treatment of achondroplasia.
Un blog dedicado al tratamiento de la acondroplasia.Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.comBlogger338125tag:blogger.com,1999:blog-4791085249231790709.post-4268534071280002532023-04-26T15:25:00.001-04:002023-04-27T13:18:53.474-04:00Treating achondroplasia: eleven years online and a view of the future.<p><span style="font-family: Overpass;">I have started this blog in March 2012, around the same time when pioneering initiatives to treat achondroplasia were just beginning to move from the lab desks to clinical development. Since then, the blog has received close to 500K visits! <br /></span></p><p><span style="font-family: Overpass;">However, reaching out to the point where we are now, with one treatment approved and being given to many children around the world, and many others in clinical trials, was not exactly easy. </span></p><p><span style="font-family: Overpass;">The cause of achondroplasia, a single point mutation in a key bone growth regulator gene,<i> FGFR3</i>, was identified in 1994 (1) but it was not until 2003 that the first attempts to control the activity of the protein<i> </i><b>fibroblast growth factor receptor 3</b> (FGFR3) were published (2). </span></p><p><span style="font-family: Overpass;">Almost 20 years after the discovery of FGFR3 as the cause of achondroplasia, the first potential treatment, vosoritide, was brought to the clinic in 2012, in a phase 1 study with healthy volunteers (NCT01590446) and then, in January 2014, to a phase 2 study which enrolled around 30 children with achondroplasia (NCT02055157) (3). </span></p><p><span style="font-family: Overpass;">That phase 2 study showed that vosoritide was able to partially restore bone growth velocity (3). In the subsequent larger phase 3 trial (4), after two years of treatment, the effects of vosoritide on bone growth in achondroplasia were considered consistent enough to grant its approval by the main drug development regulatory agencies around the world. Many children with achondroplasia are now being treated with vosoritide and there have been plenty of testimonies published in the social media about kids growing faster then they were before they started treatment.</span></p><p><span style="font-family: Overpass;">The success of vosoritide attracted other drug developers: at this moment there are at least seven known other potential therapies in development for achondroplasia:</span></p><p><span style="font-family: Overpass;">Table 1. List of therapies in development for achondroplasia (not exhaustive).</span></p><span style="font-family: Overpass;"><img alt="" height="406" 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" width="640" /></span><p><span style="font-family: Overpass;">The above table is an updated version of the one I presented during the <a href="https://www.fundacionalpe.org/es/noticias/vii-congreso-internacional-en-torno-a-las-adee-resumen">ALPE Congress</a> back in October last year (there is another <a href="https://www.treatingachondroplasia.com/2022/10/treating-achondroplasia-where-do-we-go.html">article </a>in the blog about that meeting). Since then, the developers of infigratinib (see <a href="https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-pharma-announces-positive-interim-results-phase-2">here</a>) and TransCon-CNP (see <a href="https://investors.ascendispharma.com/static-files/44b24b0c-f83d-48fa-aaef-9bdb768999d3">here</a>), have published promising results of their phase 2 studies, which will need to be confirmed in respective phase 3 trials. </span></p><p><span style="font-family: Overpass;">However, not all these initiatives have been successful. Recently, Pfizer, which was developing recifercept for achondroplasia, cancelled the program because the drug was not providing any increment on bone growth in children enrolled in their phase 2 study (see <a href="https://www.fiercebiotech.com/biotech/pfizer-punts-pair-orphan-drugs-amid-rare-disease-rd-rethink">here</a>). </span></p><p><span style="font-family: Overpass;">Meanwhile, Tyra, a small biotech from California, announced positive pre-clinical results of their TYRA-300 in an animal model of achondroplasia and their intention to take that asset to clinical development (see <a href="https://tyrabio.investorroom.com/2023-03-01-Tyra-Biosciences-Expands-Development-of-TYRA-300,-an-Oral-FGFR3-Selective-Agent,-into-Achondroplasia">here</a>). </span></p><p><span style="font-family: Overpass;">A search in the literature will also retrieve several other interesting studies evaluating different compounds that seem to have a positive impact on bone growth, directly or indirectly targeting FGFR3.</span></p><p><b style="font-family: Overpass;"><i>It's not only about height </i></b><span style="font-family: Overpass;"><br /></span></p><p><span style="font-family: Overpass;">I believe that all these work and accomplishments will certainly provide a wide range of benefits for children with achondroplasia. The impaired bone growth that is typical in achondroplasia does not cause only low final stature: there is plenty of evidence that impaired bone growth leads to a series of medical and psychological complications during the life span of affected individuals (5-7). Although it is too early to draw conclusions about any beneficial effects in other aspects linked to impaired bone growth in this skeletal dysplasia, one can estimate that, given these therapies have systemic effect, a decrease in the rate of typical orthopedic complications that affect both children and adults, such as arched legs, spinal stenosis and elbow mobility restrictions, among others, is predictable. </span></p><p><span style="font-family: Overpass;">Moreover, recently published studies have also evaluated quality-of-life (QoL) in children and adults with achondroplasia (5-7). In summary, they report that individuals with achondroplasia have lower QoL indexes compared to those of the general population. The impact on QoL has been linked to challenges with daily function, and also physical and mental health. (6,7). There is an expectation that, by improving the length of the long bones, some routine aspects of daily function such as self-hygiene may also improve. With better mobility and function, it is expected that other QoL indexes will improve as well. <br /></span></p><p><b style="font-family: Overpass;"><i>It's not only about achondroplasia</i></b><span style="font-family: Overpass;"><br /></span></p><p><span style="font-family: Overpass;">One important concept to have in
mind about bone growth is that it depends on an intricate system in
which many agents work in concert either
increasing or reducing the bone growth pace (you can read more about
this in other <a href="https://www.treatingachondroplasia.com/p/achondroplasia-english.html">articles</a> of this blog). </span><span style="font-family: Overpass;">The fact is that, possibly influenced by all the progress we see for
achondroplasia, there has been more research about the mechanism of
action of those many bone growth agents in other skeletal dysplasias,
too, including FGFR3.</span></p><p><span style="font-family: Overpass;">For instance, we now know that in several skeletal dysplasias where FGFR3 is normal, the respective causative mutations seem to lead to FGFR3 axis over-activity, thus contributing to short stature. This has been already identified in RASopathies such as Noonan Syndrome (8), in Cartilage-Hair dysplasia (9), and in diastrophic dysplasia (10). </span><span style="font-family: Overpass;"><br /></span></p><p><span style="font-family: Overpass;">Furthermore, in skeletal dysplasias where the C-type natriuretic peptide (CNP) axis is not working, drugs that target FGFR3 directly may have an important role in rescuing bone growth. As you may know, CNP regulates FGFR3 activity in normal conditions; if the CNP axis is down, FGFR3 is free to work at will, thus causing severe bone growth impairment. This crosstalk between FGFR3 and CNP was the basis of the development of vosoritide.<br /></span></p><p><span style="font-family: Overpass;">Therefore,
it is reasonable to think that there is space for the potential use of
therapies directed to control FGFR3 activity in other skeletal
dysplasias. </span><span style="font-family: Overpass;">In fact, t</span><span style="font-family: Overpass;">here is already one </span><span style="font-family: Overpass;">ongoing </span><span style="font-family: Overpass;">study with vosoritide in children bearing other skeletal dysplasias (NCT04219007) such as hypochodroplasia (which is also caused by mutations in FGFR3), RASopathies, certain CNP-related dysplasias, SHOX-related dysplasias and ACAN-related dysplasias. Preliminary results from this study have already been released, too (see <a href="https://innovationdistrict.childrensnational.org/vosoritide-shows-promise-for-children-with-certain-genetic-growth-disorders/">here</a>).</span></p><p><span style="font-family: Overpass;"><i><b>The future at our door</b><br /></i></span></p><p><span style="font-family: Overpass;">As typical in the drug development field, there might be other failures ahead. However, drugs like the CNP analogs and those which directly target FGFR3, such as infigratinib, have been showing promising results in the ongoing studies. There will be more options in a few years ahead.<br /></span></p><p><span style="font-family: Overpass;">We are also starting to see research on the gene therapy field. These new generation approaches may, in the future, help to overcome mutations that would otherwise have huge impact on QoL of affected children with many genetic conditions. </span></p><p><span style="font-family: Overpass;">From genetic eye disorders or cystic fibrosis, or Duchenne muscular distrophy, to many other situations which have few to no treatment at all, one can imagine that, when the current technological challenges are resolved, how great it will be to have the possibility to provide a functional gene, for example, to a kid with diastrophic dysplasia. </span></p><p><span style="font-family: Overpass;">Based on the current available data, it is possible to envision a time, not far away from now, where children born with many of the genetic disorders such as skeletal dysplasias will be able to enjoy life as any average kid does.<br /></span></p><p><span style="font-family: Overpass;"><b><i>The Treating Achondroplasia blog </i><br /></b></span></p><p><span style="font-family: Overpass;">Meanwhile, I will keep publishing news and reviews when relevant information about therapies for achondroplasia - and skeletal dysplasias - becomes available. Thank you for your continued interest in this blog!<br /></span></p><p><span style="font-family: Overpass;"></span></p><p><span style="font-family: Overpass;"> <b><i>References</i></b></span></p><p><span style="font-family: Overpass;">1.<a href="https://pubmed.ncbi.nlm.nih.gov/8078586/"> </a><span class="docsum-authors full-authors"><a href="https://pubmed.ncbi.nlm.nih.gov/8078586/">Rousseau F</a>, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A. </span>Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia.
<span class="docsum-journal-citation full-journal-citation">Nature 1994;371(6494):252-4.</span></span></p><p><span style="font-family: Overpass;">2. <span class="docsum-authors full-authors"><a href="https://pubmed.ncbi.nlm.nih.gov/12816345/">Aviezer D</a>, Golembo M, Yayon A.</span> Fibroblast growth factor receptor-3 as a therapeutic target for achondroplasia--genetic short limbed dwarfism. <span class="docsum-journal-citation full-journal-citation">Curr Drug Targets 2003;4(5):353-65. </span></span>
</p><p><span class="docsum-authors full-authors" style="font-family: Overpass;">3. <a href="https://pubmed.ncbi.nlm.nih.gov/31269546/">Savarirayan R</a>, Irving
M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, Le Quan Sang KH,
Dickson P, Harmatz P, Phillips J, Owen N, Cherukuri A, Jayaram K, Jeha
GS, Larimore K, Chan ML, Huntsman Labed A, Day J, Hoover-Fong J. </span><span style="font-family: Overpass;">C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. <span class="docsum-journal-citation full-journal-citation">N Engl J Med 2019;381(1):25-35.</span></span></p><p><span style="font-family: Overpass;">4. <span class="docsum-authors full-authors"><a href="https://pubmed.ncbi.nlm.nih.gov/32891212/">Savarirayan R</a>, Tofts
L, Irving M, Wilcox W, Bacino CA, Hoover-Fong J, Ullot Font R, Harmatz
P, Rutsch F, Bober MB, Polgreen LE, Ginebreda I, Mohnike K, Charrow J,
Hoernschemeyer D, Ozono K, Alanay Y, Arundel P, Kagami S, Yasui N, White
KK, Saal HM, Leiva-Gea A, Luna-González F, Mochizuki H, Basel D, Porco
DM, Jayaram K, Fisheleva E, Huntsman-Labed A, Day J.</span> Once-daily, subcutaneous <b>vosoritide</b> therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.
<span class="docsum-journal-citation full-journal-citation">Lancet. 2020;396(10252):684-92.</span></span></p><p><span style="font-family: Overpass;">5.<a href="https://pubmed.ncbi.nlm.nih.gov/34837063/"> </a><span class="docsum-authors full-authors"><a href="https://pubmed.ncbi.nlm.nih.gov/34837063/">Savarirayan R</a>, Ireland
P, Irving M, Thompson D, Alves I, Baratela WAR, Betts J, Bober MB,
Boero S, Briddell J, Campbell J, Campeau PM, Carl-Innig P, Cheung MS,
Cobourne M, Cormier-Daire V, Deladure-Molla M, Del Pino M, Elphick H,
Fano V, Fauroux B, Gibbins J, Groves ML, Hagenäs L, Hannon T,
Hoover-Fong J, Kaisermann M, Leiva-Gea A, Llerena J, Mackenzie W, Martin
K, Mazzoleni F, McDonnell S, Meazzini MC, Milerad J, Mohnike K, Mortier
GR, Offiah A, Ozono K, Phillips JA 3rd, Powell S, Prasad Y, Raggio C,
Rosselli P, Rossiter J, Selicorni A, Sessa M, Theroux M, Thomas M,
Trespedi L, Tunkel D, Wallis C, Wright M, Yasui N, Fredwall SO.</span> International Consensus Statement on the diagnosis,
multidisciplinary management and lifelong care of individuals with achondroplasia. <span class="docsum-journal-citation full-journal-citation">Nat Rev Endocrinol 2022 Mar;18(3):173-89.</span></span></p><p><span style="font-family: Overpass;">6. <a href="https://pubmed.ncbi.nlm.nih.gov/34403286/">Constantinides C</a>, Landis SH, Jarrett J, Quinn J, Ireland PJ. Quality of life, physical functioning, and psychosocial function among
patients with achondroplasia : a targeted literature review. <span class="period">Disab Rehabil </span><span class="cit">2022;44(21):6166-78.</span></span>
</p><span style="font-family: Overpass;">7. <a href="https://pubmed.ncbi.nlm.nih.gov/33369042/">Yonko EA</a>, Emanuel JS, Carter EM, Raggio CL. Quality of life in adults with achondroplasia in the United States. <span class="period">Am J Med Genet A </span><span class="cit">2021;185(3):695-701.</span></span>
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</div><p><span style="font-family: Overpass;">8. <span class="docsum-authors full-authors"><a href="https://pubmed.ncbi.nlm.nih.gov/23571107/">Ono K</a>, Karolak MR, Ndong Jde L, Wang W, Yang X, Elefteriou F.</span>The ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation. <span class="docsum-journal-citation full-journal-citation">Hum Mol Genet. 2013;22(15):3048-62.</span></span></p><p><span class="docsum-journal-citation full-journal-citation" style="font-family: Overpass;">9. </span><span style="font-family: Overpass;"><a href="https://pubmed.ncbi.nlm.nih.gov/34988338/">Chabronova A</a>, </span><span class="docsum-authors full-authors"><span style="font-family: Overpass;">van den Akker GGH,
Meekels-Steinbusch MMF, Friedrich F, Cremers A, Surtel DAM, Peffers MJ,
van Rhijn LW, Lausch E, Zabel B, Caron MMJ, Welting TJM</span>.</span><span style="font-family: Overpass;"> Uncovering pathways regulating chondrogenic differentiation of CHH fibroblasts Non-coding RNA Res 2021;6(4):211-24. </span></p><div class="publication-title u-h3" id="publication-title" style="text-align: left;"><span style="font-family: Overpass;">10. <a href="https://pubmed.ncbi.nlm.nih.gov/30685387/">Zheng C</a>. <span class="authors-list-item">Lin X<span class="comma">, </span></span><span class="authors-list-item">Xu X<span class="comma">,</span></span><span class="authors-list-item"> Wang C<span class="comma">, </span></span><span class="authors-list-item">Zhou J<span class="comma">, </span></span><span class="authors-list-item">Gao B<span class="comma">, </span></span><span class="authors-list-item">Fan J<span class="comma">, </span></span><span class="authors-list-item">Lu W<span class="comma">, </span></span><span class="authors-list-item">Hu Y<span class="comma">, </span></span><span class="authors-list-item">Jie Q<span class="comma">, </span></span><span class="authors-list-item">Luo Z<span class="comma">, </span></span><span class="authors-list-item">Yang L. </span>Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine. 2019 Feb;40:695-709. </span></div><div class="publication-title u-h3" id="publication-title" style="text-align: left;"><span style="font-family: Overpass;"> </span></div><div class="publication-title u-h3" id="publication-title" style="text-align: left;"> </div><div class="publication-title u-h3" id="publication-title" style="text-align: left;"> </div><div class="publication-title u-h3" id="publication-title" style="text-align: left;"> </div>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-90767533938029186572022-11-15T21:38:00.001-05:002022-11-15T21:39:00.140-05:00Treating achondroplasia: Ascendis releases outcomes of the phase 2 study with TransCon-CNP<p><span style="font-family: Roboto;"><b><i>The ACcomplisH trial </i></b><br /></span></p><p><span style="font-family: Roboto;"> On November 13th, Ascendis Pharma released top line results of the ongoing phase 2 study with TransCon-CNP, an analog of c-type natriuretic peptide (CNP) wrapped in a transport molecule to allow slow-release and extend the half-life of the analog. </span></p><p><span style="font-family: Roboto;">Let's pause here for a moment as in this first sentence there is a lot of information already. </span></p><p><span style="font-family: Roboto;">In other words, TransCon-CNP is a competitor of vosoritide. The main difference between them is that the CNP analog from Ascendis uses a kind of taxi: its CNP analog is covered by a molecule that serves as a protection against the body clearance systems, so it has an extended time to exert its actions. The taxi allows the Ascendis CNP analog to be given just once a week as opposed to vosoritide, which needs to be administered daily.</span></p><p><span style="font-family: Roboto;">As typical of phase 2 studies, the ACcomplisH trial was designed to evaluate several different doses to TransCon-CNP in order to define which one would have the best safety/efficacy profile.</span></p><p><span style="font-family: Roboto;">In summary, these are the headlines directly from Ascendis <a href="https://investors.ascendispharma.com/news-releases/news-release-details/once-weekly-transcontm-cnp-achieved-primary-efficacy-objective">press release</a>: </span></p><ul style="text-align: left;"><li><span style="font-family: Roboto;">In the Phase 2 ACcomplisH Trial in children with achondroplasia aged 2-10, once-weekly TransCon CNP demonstrated the potential to meet patient and caregiver needs for a safe, effective, tolerable, and convenient treatment</span><br /><span style="font-family: Roboto;"></span></li></ul><ul style="text-align: left;"><li><span style="font-family: Roboto;">The primary endpoint, annualized height velocity (AHV) at Week 52, demonstrated superiority of TransCon CNP at 100 μg/kg/week compared to placebo (p=0.0218)</span></li></ul><ul style="text-align: left;"><li><span style="font-family: Roboto;">TransCon CNP was generally well tolerated with low frequency of injection site reactions; all 57 randomized children continued, with the longest treatment duration beyond two years</span><br /><span style="font-family: Roboto;"></span></li></ul><ul style="text-align: left;"><li><span style="font-family: Roboto;">Data showed robust and consistent results in prespecified analyses across age groups and dose levels, supporting continued development at the selected dose of 100 μg/kg/week<br /></span></li></ul><p><span style="font-family: Roboto;"> <i><b>Efficacy </b></i><br /></span></p><p><span style="font-family: Roboto;">Three of the four doses tested lead to growth improvement but only the highest one was found to be significantly superior to placebo (Table 1).</span></p><p><span style="font-family: Roboto;">It is important to learn that TransCon-CNP worked similarly in all age groups tested. <br /></span></p><p><span style="font-family: Roboto;">Table 1. Efficacy of TransCon-CNP weekly doses (from the AComplisH study <a href="https://investors.ascendispharma.com/static-files/44b24b0c-f83d-48fa-aaef-9bdb768999d3" target="_blank">presentation</a>).<br /></span></p><p><span style="font-family: Roboto;"><img alt="" height="237" src="data:image/png;base64,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" width="640" /> </span></p><p><span style="font-family: Roboto;"></span></p><p><i><b><span style="font-family: Roboto;">Safety</span></b></i></p><p><span style="font-family: Roboto;">The press release informs us that TransCon-CNP was well tolerated. Most of the few adverse events </span><span style="font-family: Roboto;">reported </span><span style="font-family: Roboto;">were related to local injection site reactions.</span></p><p><span style="font-family: Roboto;"><i><b>Next steps</b></i><br /></span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;">Based on the results of this study Ascendis informed that they are in conversations with regulators and also enrolling patients in their phase 2B study to further investigate the chosen dose for achondroplasia (100 µg/kg/week).</span></p><p><span style="font-family: Roboto;"><i><b>Context</b></i><br /></span></p><p><span style="font-family: Roboto;">As we can see in Table 1, children the highest dose of TransCon-CNP </span><span style="font-family: Roboto;">on average</span><span style="font-family: Roboto;"> grew 1.07cm </span><span style="font-family: Roboto;"> (24.6%) </span><span style="font-family: Roboto;">more than those in placebo. This is lower than what was obtained with vosoritide in its phase 3 study (1,2), which you can see below (transcript from the original <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327889/" target="_blank">publication</a>;(2)):</span></p><ul style="text-align: left;"><li><span style="font-family: Roboto;"><i>In the placebo-controlled study, children randomized to treatment with vosoritide increased annualized growth velocity to 5.96 (1.51) cm/year at 26 weeks and 5.39 (1.87) cm/year at 52 weeks. In children randomized to placebo the annualized growth velocity was 4.08 (1.36) cm/year at 26 weeks and 3.81 (1.31) cm/year at 52 weeks. </i><br /></span></li></ul><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;">Based on what we have already seen with vosoritide trials, o</span><span style="font-family: Roboto;">ne aspect to have in consideration is that there is a large variability of response to treatment (just look at the growth ranges among the treated groups in Table 1). This was also seen in vosoritide studies. <br /></span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;"></span><span style="font-family: Roboto;">The population treated in the phase 2
study with TransCon-CNP is considerably smaller than the one in the
phase 3 vosoritide trial, but the results show the potential efficacy of
the chosen dose that we would expect in the ongoing phase 2B study. It
would be interesting to learn why the developer did not consider
evaluating a higher dose of TransCon-CNP, as it is possible that its
optimal dose (efficacy+safety) might not have been identified yet. <br /></span></p><p><span style="font-family: Roboto;">One relevant advantage of TransCon-CNP is its weekly dosing schedule, which would be likely considered more comfortable by parents and individuals than vosoritide's daily injection. </span></p><p><span style="font-family: Roboto;">Finally, if TransCon-CNP would be able to provide consistent growth in longer term (as we might see in the next step of its clinical development), and taking in account that it has been showing to work positively in younger kids, it might become a fair option to vosoritide in the future, even if the nominal growth increment was lower in the phase 2 study compared to the already approved treatment.<br /></span></p><p><i><b><span style="font-family: Roboto;">References</span></b></i></p><p><span style="font-family: Roboto;"> 1. <a href="https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(20)31541-5" target="_blank">Savarirayan R et al</a>. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; Oct 10;396(10257):1070. <i>Free access.</i></span></p><p><span style="font-family: Roboto;"><i>2. </i><a href="https://linkinghub.elsevier.com/retrieve/pii/S1098-3600(21)05439-3" target="_blank">Savarirayan R et al</a>. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med 2021 Dec;23(12):2443-47. </span><span style="font-family: Roboto;"><i>Free access.</i></span></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-31545080843093737042022-10-20T22:24:00.006-04:002023-04-24T18:18:08.408-04:00Treating achondroplasia: where do we go from here?<div class="separator"><span style="font-size: small;"><span style="font-family: Roboto;">Just a few days ago, Fundación Alpe Acondroplasia was inaugurating its seventh international congress about skeletal dysplasias (<a href="http://www.congresoalpe2022.com/">http://www.congresoalpe2022.com/</a>). Top experts from all over the world came together to present current best practices in the healthcare for achondroplasia and skeletal dysplasias and talk about the advances seen in the last decade. </span></span></div><div class="separator"><span style="font-size: small;"><span style="font-family: Roboto;"> </span></span></div><div class="separator"><span style="font-size: small;"><span style="font-family: Roboto;">Drug developers provided updates about their current work. Most importantly, the congress brought to Gijón, the charming Asturian town home of Alpe (Figure 1), leaders from many parts of the globe to discuss the main challenges those with skeletal dysplasias face in a daily basis, from social discrimination and political issues to access to appropriate healthcare in their countries.</span></span></div><div class="separator"><span style="font-size: small;"><span style="font-family: Roboto;"> </span></span></div><div class="separator"><span style="font-family: Roboto;"> </span></div><div class="separator"><span style="font-family: Roboto;">Figure 1. Gijón, Spain.</span></div><div class="separator"><span style="font-family: Roboto;"> <br /></span></div><div class="separator"><span style="font-family: Roboto;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgU7xhvovw0g-k-1hlIdir04fD44fwkx3n5uEQ0nf_9NV40gcfzOzrOf9dH2sNyUNQUUq-GqP7BND5JFbZSXaRgrtck8lsxVKaCf9wNjZ2EMPg08EPd0AN7QyUTXFThyovkcB9K7oCSdT1conUGx3hBDkLXYX1QLlwtFOThbDx5m6grTEPJiHXr0Ar8/s2048/IMG_2029.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="1536" data-original-width="2048" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgU7xhvovw0g-k-1hlIdir04fD44fwkx3n5uEQ0nf_9NV40gcfzOzrOf9dH2sNyUNQUUq-GqP7BND5JFbZSXaRgrtck8lsxVKaCf9wNjZ2EMPg08EPd0AN7QyUTXFThyovkcB9K7oCSdT1conUGx3hBDkLXYX1QLlwtFOThbDx5m6grTEPJiHXr0Ar8/w400-h300/IMG_2029.jpg" width="400" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Gijón, Spain.<br /></td></tr></tbody></table><br /> </span></div><p><span style="font-family: Roboto;">Fundación Alpe has been a stronghold for skeletal dysplasias throughout the years, with a clear vision of what is needed today to improve the lives of people with skeletal dysplasias but also with an understanding that, as science evolves, what is considered standard now may become obsolete in the future. I believe that vision explains why they set <i>Alpe y un nuevo horizonte</i> (Alpe and a new horizon) as the signature for this edition of the congress.</span></p><p><span style="font-family: Roboto;">As a member of Alpe's Scientific Advisory Board, I was asked to talk about the changing scenery in the healthcare for achondroplasia and skeletal dysplasias. </span><span style="font-family: Roboto;">I am grateful to the strong leaders
of Fundación Alpe, Carmen Alonso Alvarez and Susana Noval Iruretagoyena
for the opportunity to talk about the current status of
pharmacological therapies for achondroplasia and future perspectives
during the congress. </span></p><p><span style="font-family: Roboto;">Here I share my presentation with our 17 readers, hoping that the topics discussed there (and here) will help families interested in therapies for skeletal dysplasias to stay updated about the developments we are seeing in the field.</span></p><p><span style="font-family: Roboto;">So, where do we go from here?</span></p><p><span style="font-family: Roboto;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjZ3phjDCxsLduKRK4CQb_dPz3LjZIhjHrFtG1hn_m0tSuXYgD_2DT8O7t9TfcbmLr5my-MrRqNFuudeHOtDbRzfqNGRV5Oqqm_ZSzeqk5Km1k-HkuglE4bTaLfSUajPDSXOOm9uzDmhzFV33ZZcDtOwfZi6uUnwKbF8Q5TfDa2RA_vRF0pGxma6lMN/s1280/MKAlpe2022Slide1.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="694" data-original-width="1280" height="347" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjZ3phjDCxsLduKRK4CQb_dPz3LjZIhjHrFtG1hn_m0tSuXYgD_2DT8O7t9TfcbmLr5my-MrRqNFuudeHOtDbRzfqNGRV5Oqqm_ZSzeqk5Km1k-HkuglE4bTaLfSUajPDSXOOm9uzDmhzFV33ZZcDtOwfZi6uUnwKbF8Q5TfDa2RA_vRF0pGxma6lMN/w640-h347/MKAlpe2022Slide1.jpg" width="640" /></a></div><p></p><p><span style="font-family: Roboto;">Achondroplasia has been known for thousand of years. Archeological treasures have been found in all continents depicting the typical features of this skeletal dysplasias (Slide 1).</span></p><p><span style="font-family: Roboto;"> Slide 1. Achondroplasia has been depicted by many ancient cultures all over the world. <br /></span></p><p><span style="font-family: Roboto;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4cjzGkPgmaX_uYJ3fcHqPu2NWzfLFZookOY4AiGeyDlb2tKNX1iluYTZ5y2ISrxO84sMn_SDYf1Egu7IXiYp1g4kVgeQfIrTxYCWXe3YGOFbDg_5QZ_z3f2P1_S8c7l4Bb4V_XMWb5R2LWW1jYvXVhWlHZUpPiY2L53kLITrHwRrHwcJS7h_su_Av/s1280/MKAlpe2022Slide3.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4cjzGkPgmaX_uYJ3fcHqPu2NWzfLFZookOY4AiGeyDlb2tKNX1iluYTZ5y2ISrxO84sMn_SDYf1Egu7IXiYp1g4kVgeQfIrTxYCWXe3YGOFbDg_5QZ_z3f2P1_S8c7l4Bb4V_XMWb5R2LWW1jYvXVhWlHZUpPiY2L53kLITrHwRrHwcJS7h_su_Av/w640-h360/MKAlpe2022Slide3.jpg" width="640" /></a></div><p></p><p><span style="font-family: Roboto;"><b><i> A long journey</i></b><br /></span></p><p><span style="font-family: Roboto;">The term achondroplasia was used for the first time in 1878 by the French doctor Jean Parrot to describe a condition where there was <i>no cartilage growth</i> (Slide 2). <br /></span></p><p><span style="font-family: Roboto;">It took more than a hundred years from that first paper for science to identify the gene mutation that causes achondroplasia. A recurrent, single point mutation in the gene which encodes the enzyme <i>Fibroblast Growth Factor Receptor 3</i> (FGFR3) was finally linked to achondroplasia in 1994. After that, scientists quickly learned that the recurrent G380R mutation in FGFR3 makes this receptor enzyme excessively active leading to bone growth arrest. <br /></span></p><p><span style="font-family: Roboto;">Meanwhile, a few pioneers started to study the mutation and almost ten years later the first attempts to find therapies were published. In 2003, Dr. Yayon group designed the first antibody against FGFR3 while the Japanese group leaded by Dr. Nakao released the first study with C-type natriuretic peptide (CNP) in the cartilage growth plate. CNP was discovered to antagonize the activity of FGFR3 in the growth plate and this lead to further discoveries.<br /></span></p><p><span style="font-family: Roboto;">In 2010, Biomarin introduced a first CNP analog, BMN-111, in their pipeline. In 2014 they started the first study of BMN-111 (now known as vosoritide) in children with achondroplasia. Finally, in 2021, after a long clinical development journey, vosoritide was approved by major regulatory agencies and is already being used in several countries for the treatment of achondroplasia. <br /></span></p><p><span style="font-family: Roboto;">Slide 2. A timeline of achondroplasia. <br /></span></p><div class="separator" style="clear: both; text-align: left;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjtVHM5FxMx1b7fUZCglUrY3y5ABT7wo42S6aHuk4NeTkATdazkTyv2HWvk7cJ043ihe0bfopFptL1RqyCUgJS6_-TqrqtKfnigHm4bRNvNk4HcZwgtlRBwRUUtj9abCZLzq75zvklzVjuIM-cupCSOYa6VwseJ4d7zA92AzNUQUuGA7NftP_xrGbwb/s1280/MKAlpe2022Slide4.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="688" data-original-width="1280" height="344" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjtVHM5FxMx1b7fUZCglUrY3y5ABT7wo42S6aHuk4NeTkATdazkTyv2HWvk7cJ043ihe0bfopFptL1RqyCUgJS6_-TqrqtKfnigHm4bRNvNk4HcZwgtlRBwRUUtj9abCZLzq75zvklzVjuIM-cupCSOYa6VwseJ4d7zA92AzNUQUuGA7NftP_xrGbwb/w640-h344/MKAlpe2022Slide4.jpg" width="640" /></a><span style="font-family: Roboto;">One aspect of the scientific research about achondroplasia is that the interest about this skeletal dysplasia got a booster after the announcement of the phase 2 study of vosoritide (Slide 3). Someone reviewing the scientific activity about achondroplasia might reach the conclusion that the increased interest was mostly driven by drug developers introducing new potential therapies. This is only partially true. In fact, although it has been recognized that achondroplasia is the most common form of skeletal dysplasia, and that a relatively fair knowledge about its typical clinical features were already in place in 2004, many questions regarding clinical and developmental aspects were still poorly addressed. In the last few years many publications have focused on epidemiological, clinical and developmental aspects of achondroplasia rather than simply working with potential therapies (Slides 4 and 5).</span><span style="font-family: Roboto;"> <br /></span></div><p><span style="font-family: Roboto;">Slide 3. The number of publications about achondroplasia has been rising in the last ten years.<br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjG2e6-aEYviwy-tXpsIl-w5nxucH-BCMD78FoTnl9seSypD-wHDPS9D4mWvHKspJdlVafuTX6ADwFhDdvNAypVS542IZaSWiRQ5mMa4GLut_2LvrdWlvljQKvhDUnTBmxZ_gI3Wfmiaa5gVueYcoLundQufaY5cRz0Xg5QZSDvJ_OKs1V6maMfXDZF/s1280/MKAlpe2022Slide5.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="702" data-original-width="1280" height="352" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjG2e6-aEYviwy-tXpsIl-w5nxucH-BCMD78FoTnl9seSypD-wHDPS9D4mWvHKspJdlVafuTX6ADwFhDdvNAypVS542IZaSWiRQ5mMa4GLut_2LvrdWlvljQKvhDUnTBmxZ_gI3Wfmiaa5gVueYcoLundQufaY5cRz0Xg5QZSDvJ_OKs1V6maMfXDZF/w640-h352/MKAlpe2022Slide5.jpg" width="640" /> </a></div><div class="separator" style="clear: both; text-align: center;"> <br /></div><div style="text-align: left;"><span style="font-family: Roboto;"></span></div><div style="text-align: left;"><span style="font-family: Roboto;"><div class="separator" style="clear: both; text-align: center;"></div></span></div><div style="text-align: left;"><span style="font-family: Roboto;"><br />Slide 4. Research on drug therapies for achondroplasia leads to improvement in healthcare. </span><br /></div><p><span style="font-family: Roboto;"><br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiT9_Aq8r_cL_Fm3JRWvmFLp96H4aNQMSSNgBC8TeWfs0bXAbwH97cYkvdy3iDLWvk103H-63nHA526MjcYJ3LLyC8opMv_WijwPlIL3hHf0nhEz1uLLL6gcljGHbmNdK89x7Zsvo6miI78e8LLPFXCFiNpTtCoCgWpfaP6j6mZ7NSfi_jeAHM3FTpS/s1280/MKAlpe2022Slide6.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="691" data-original-width="1280" height="346" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiT9_Aq8r_cL_Fm3JRWvmFLp96H4aNQMSSNgBC8TeWfs0bXAbwH97cYkvdy3iDLWvk103H-63nHA526MjcYJ3LLyC8opMv_WijwPlIL3hHf0nhEz1uLLL6gcljGHbmNdK89x7Zsvo6miI78e8LLPFXCFiNpTtCoCgWpfaP6j6mZ7NSfi_jeAHM3FTpS/w640-h346/MKAlpe2022Slide6.jpg" width="640" /></a></div> <p></p><p><span style="font-family: Roboto;">Slide 5. The first International Consensus for the management of achondroplasia.<br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgVPqp9GkWxCmy9HxgYDaIBMMPuAAeCb2y6AMd1pJOZ0mN9NkNDxu_1rLSBSkf13FFFcC_p_ugVFKy104FkaIiaE9vBQ3VlF1XPW0uB-n2CATJs9iaw2EzVWgD55PusXCFeltkat9vOzMuoNAukfAqAeMNYEwE-vWOTgBXWG9tLWHJs_MKMFEbAHR3t/s1280/MKAlpe2022Slide7.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="693" data-original-width="1280" height="346" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgVPqp9GkWxCmy9HxgYDaIBMMPuAAeCb2y6AMd1pJOZ0mN9NkNDxu_1rLSBSkf13FFFcC_p_ugVFKy104FkaIiaE9vBQ3VlF1XPW0uB-n2CATJs9iaw2EzVWgD55PusXCFeltkat9vOzMuoNAukfAqAeMNYEwE-vWOTgBXWG9tLWHJs_MKMFEbAHR3t/w640-h346/MKAlpe2022Slide7.jpg" width="640" /></a></div><p></p><p><span style="font-family: Roboto;"> </span></p><p><span style="font-family: Roboto;"><i><b>Real people. Real problems.</b></i><br /></span></p><p><span style="font-family: Roboto;">Why are these new guidelines and a first international consensus on healthcare for achondroplasia so important? </span></p><p><span style="font-family: Roboto;">In the real life, daily medical and social challenges are common place both for children and adults with achondroplasia (Slide 6 just provides a few examples extracted from social media). These new publications aim to address the key medical elements that may improve health and quality of life spanning all age groups. It is clear that we need to do better.<br /></span></p><p><span style="font-family: Roboto;">Slide 6. Real people. Real problems.<br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCqlhsvKZGA071s2fEo8VFwBt_vauvxGRjelUkLnMl8CLcFZ3sqa6d1n6n7B6qyTIrzFgZE78ensO3-uIOlRtU5WqJ6uuG88ID42yaUfAU0dSRncWPDjXM7zEOg20N7H9kYutoybRkf44QenRLUsnaQbud0y9_UtQ6_uuGhQxoiR_07aIifA1dJIG4/s1280/MKAlpe2022Slide8.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCqlhsvKZGA071s2fEo8VFwBt_vauvxGRjelUkLnMl8CLcFZ3sqa6d1n6n7B6qyTIrzFgZE78ensO3-uIOlRtU5WqJ6uuG88ID42yaUfAU0dSRncWPDjXM7zEOg20N7H9kYutoybRkf44QenRLUsnaQbud0y9_UtQ6_uuGhQxoiR_07aIifA1dJIG4/w640-h360/MKAlpe2022Slide8.jpg" width="640" /></a></div><p></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;"><i><b>Progress</b></i></span></p><p><span style="font-family: Roboto;">While learning and understanding the natural history of achondroplasia will certainly lead to better healthcare, it is undeniable that the research towards solutions to control the overactive FGFR3 are in full speed right now, with many potential therapies in various degrees of development (Slide 7).</span></p><p><span style="font-family: Roboto;"> Slide 7. Current and potential therapies for achondroplasia. <br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiV6xqYRoZN5QpEYnrL7vQ-Kla6BA8DzQTFTqJkDRl8EduTOm6Ie3qOOPtnayz3RlQTJkT4m1Bmv54vhMwiAjIyGEWW3uu0potBvt0t86Mck6X-9JH-kv4D5oC9uLLuyq1igwZAaTG2nfsLo7KKk4yuGHGhshajzhAlMZRdas3XxBgHJ1hDylyZM8hE/s1280/MKAlpe2022Slide9.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiV6xqYRoZN5QpEYnrL7vQ-Kla6BA8DzQTFTqJkDRl8EduTOm6Ie3qOOPtnayz3RlQTJkT4m1Bmv54vhMwiAjIyGEWW3uu0potBvt0t86Mck6X-9JH-kv4D5oC9uLLuyq1igwZAaTG2nfsLo7KKk4yuGHGhshajzhAlMZRdas3XxBgHJ1hDylyZM8hE/w640-h360/MKAlpe2022Slide9.jpg" width="640" /></a></div><p></p><p><span style="font-family: Roboto;">As we know, last year vosoritide was approved for the treatment of achondroplasia based on its positive effects on bone growth velocity and incremental and sustained growth over two years (Slide 8). There was some controversy about choosing growth velocity as a parameter of efficacy without observing other clinical aspects that are relevant in achondroplasia. However, having in mind that bone growth is a slow process, using changes in growth velocity seems to be a reasonable way to verify efficacy in relatively short term. The known clinical complications seen in achondroplasia are frequently related to restricted bone growth. It is possible that over years (so long term) we may see that these complications will become less prevalent, but this will take some time more to be confirmed.</span></p><p><span style="font-family: Roboto;">Furthermore, if </span><span style="font-family: Roboto;">together with improvement in standing height,</span><span style="font-family: Roboto;"> we expect that there will be a reduction in the frequency of medical issues in children receiving pharmacological therapy, then another aspect that should also improve is quality-of-life (as measured through several tools), which is known to be lower in achondroplasia compared to the general population.<br /></span></p><p><span style="font-family: Roboto;">Another important question that needs to be addressed has to do with an understandable but unrealistic expectation many parents may have today about the results of any pharmacological therapy (Slide 8). Having their child under drug treatment should not preclude the need for continuous specialized follow up, at least for the next few years, until we get more evidence that the treatment may really reduce the incidence of orthopedic and neurological complications. Let's say we need to wait and see whether the treatment could bring the child to a level of healthcare need that is typical of the average child. So, as for now, just pharmacological treatment is not enough.<br /></span></p><p><span style="font-family: Roboto;"> </span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;">Slide 8. The changing landscape.</span></p><p><span style="font-family: Roboto;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiTTo2nCzRIdVCEm1zHO56Q4BFHawkrQ9Hqmq0K0x5uP38w-BfQ0yWCkEwEP_Ph6RQjqFLFgIeIYD6WCGUANMqKPFeZO_TxAE5LvrLOC1lM4ClvTZ26E6wNRFS1QFjdjG6w6khEafdTzrUenLLMhcmQlq3vxE3Sosxni9pJ1zH4gV8_bt90EPVHx1C-/s1280/MKAlpe2022Slide10.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiTTo2nCzRIdVCEm1zHO56Q4BFHawkrQ9Hqmq0K0x5uP38w-BfQ0yWCkEwEP_Ph6RQjqFLFgIeIYD6WCGUANMqKPFeZO_TxAE5LvrLOC1lM4ClvTZ26E6wNRFS1QFjdjG6w6khEafdTzrUenLLMhcmQlq3vxE3Sosxni9pJ1zH4gV8_bt90EPVHx1C-/w640-h360/MKAlpe2022Slide10.jpg" width="640" /></a></div><p></p><p><span style="font-family: Roboto;">So, where are we now and where do we go from here? (Slide 9)<br /></span></p><p><span style="font-family: Roboto;">As countries approve and include vosoritide within their pharmacopeias, there have been many questions raised on social media related to access to treatment. Vosoritide is a high cost medicine, at a level that is not affordable for the vast majority of families interested in offering this option to their children. The developer and payers must find a common ground where the reward for being the pioneer in the field is well paid off while access is amplified. </span></p><p><span style="font-family: Roboto;">However, access is only one the challenges ahead. The social media is indeed a source of helpful information (at least related to our topic here). An issue that has been raised by families looking for treatment for their kids is the little, if any, knowledge professionals that assist kids with achondroplasia have been demonstrating about the new pharmacological therapy and healthcare management in general. Since experts in skeletal dysplasias usually work in specialized referral centers, effort needs to be done to spread more effectively the knowledge not only about pharmacological therapies but also on the management of achondroplasia in the primary or secondary care settings. This, in turn, may also help improving access to therapies. Statement papers and the Consensus depicted in slides 4 and 5 may be a good starting point to extend the knowledge gained in recent years to the front-line of healthcare.<br /></span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;"></span></p><p><span style="font-family: Roboto;">Slide 9. The future of healthcare for skeletal dysplasias.<br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgRrLWfYuM2_f4KPBHvCOSbNjSNnnaK2NnwT90wVYhSwHiLK1c64hRfTn8WuM-5DoLsLJdjukqGN65s80tx2hldZ86qtD9fw4_7ip0B2eM_DdTkFyrG5J4Y-WU28j7N_HSJRkKphUYAGSHvX63_xaPRrC4E5eWOWmrhznEJQjTO-gL29sIEwdWBS3kl/s1280/MKAlpe2022Slide11.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgRrLWfYuM2_f4KPBHvCOSbNjSNnnaK2NnwT90wVYhSwHiLK1c64hRfTn8WuM-5DoLsLJdjukqGN65s80tx2hldZ86qtD9fw4_7ip0B2eM_DdTkFyrG5J4Y-WU28j7N_HSJRkKphUYAGSHvX63_xaPRrC4E5eWOWmrhznEJQjTO-gL29sIEwdWBS3kl/w640-h360/MKAlpe2022Slide11.jpg" width="640" /></a></div><i><b> </b></i><p></p><p><span style="font-family: Roboto;"><i><b>A new horizon</b></i></span></p><p><span style="font-family: Roboto;">Finally, as Alpe has envisioned in the recent conference, a new horizon is ahead. With all the research performed to understand the FGFR3 mutation in achondroplasia, how it works and affects bone growth, much has been learned about the overall bone growth and development process. </span></p><p><span style="font-family: Roboto;">The FGFR3 pathway is a powerful growth brake in the cartilage growth plate. It is a very important modulator of bone growth working to balance the activity of several other agents that promote bone growth. If it is working less than normal bones grow excessively and may cause medical issues; the same occurs when it is working too much as we see in achondroplasia.</span></p><p><span style="font-family: Roboto;">We now know that FGFR3 activity can be controlled. The question is whether this knowledge can be used to see if controlling FGFR3 activity would be helpful for other skeletal dysplasias. The answer to this question is yes (Slide 10). </span></p><p><span style="font-family: Roboto;">It would be common sense to deduct that other skeletal dysplasias where in some way the FGFR3 pathway is unbalanced could be managed by vosoritide or other drugs in test for achondroplasia. For instance, other FGFR3-related dysplasias such as hypochondroplasia or other very rare cases where FGFR3 mutations cause proportionate short stature. </span></p><p><span style="font-family: Roboto;">Another example would be the CNP-related dysplasias. In these cases, most of the time the mutation causing the dysplasia is located in the CNP receptor, so giving CNP analogs would not likely help improving bone growth, but agents targeting FGFR3 directly, such as infigratinib, could be helpful.</span></p><p><span style="font-family: Roboto;">Another example shown in Slide 10 are the RASopathies, such as Noonan syndrome, where the same enzymes (the MAPK pathway) activated by FGFR3 are overactive due to mutations in regulatory proteins. In this case inhibiting FGFR3 could help reducing MAPK activity to improve bone growth.</span></p><p><span style="font-family: Roboto;">Other skeletal dysplasias might benefit of the use of anti-FGFR3 agents and there is already evidence in the literature, for instance in diastrophic dysplasia and in Mckusick syndrome, that FGFR3 might be overactive and contributing to impaired bone growth.</span></p><p><span style="font-family: Roboto;">It is also foreseeable that treatments developed for achondroplasia might benefit children born with other bone growth impairment conditions. It is time to multiply the efforts to evaluate these new potential therapies for other skeletal dysplasias.<br /></span></p><p><span style="font-family: Roboto;"> Slide 10. Treating other skeletal dysplasias<br /></span></p><p><span style="font-family: Roboto;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg3rp9s65bckxkXaUygDeIBdmiJxrq_8VbZEpzfQVCM2xbcsv-mmXTFcIIofwg-6tQaeMcstEk1e8YZH9qQI12ZRwD2-LBDHrY0nxGBeOAtyEqZgkkuHhzXn4znM46o2rsS_xMnE88oxxNVdqOVpDKxDqGD7dcQb0X4HuZ4K75MGNmZcFAdD90mHv3-/s1280/MKAlpe2022Slide12.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="693" data-original-width="1280" height="346" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg3rp9s65bckxkXaUygDeIBdmiJxrq_8VbZEpzfQVCM2xbcsv-mmXTFcIIofwg-6tQaeMcstEk1e8YZH9qQI12ZRwD2-LBDHrY0nxGBeOAtyEqZgkkuHhzXn4znM46o2rsS_xMnE88oxxNVdqOVpDKxDqGD7dcQb0X4HuZ4K75MGNmZcFAdD90mHv3-/w640-h346/MKAlpe2022Slide12.jpg" width="640" /></a></div><br /> <br /><p></p><p></p><p><span style="font-family: Roboto;"> </span></p><p><span style="font-family: Roboto;"><i><b>The future is around the corner</b></i></span></p><p><span style="font-family: Roboto;">Skeletal dysplasias are disorders which affect the body in development. These pharmacological therapies may, in the near future, help children to grow better, bringing together many benefits that go beyond achieving a higher final stature. One of them, which I have already referred to in the past, is very simple. Let's just imagine a time where a child with achondroplasia will be living the same ups and downs any average child lives as they grow into adulthood. No more, no less. I think this is a good perspective to have.</span></p><p><span style="font-family: Roboto;"><br /></span></p><p><br /></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-15593088646059596162022-02-12T15:35:00.002-05:002022-03-04T15:10:25.364-05:00Treating Achondroplasia: ten years online. A review of the current achondroplasia therapy landscape<p><span style="font-family: Roboto;"><i><b>Ten years in a row</b></i><br /><br />The blog Treating achondroplasia is celebrating 10 years online. I have not been posting as often as some years ago but I keep my eyes open to all new relevant information that comes to the field and share them with the interested reader here. </span></p><p><span style="font-family: Roboto;">Ten years ago, I started this blog with the main objective of translating the hard jargon that is typical in scientifc publications into a more relatable language that could be accessible to all. The blog has received more than 430K visits since its launch and </span><span style="font-family: Roboto;">I hope it has been a helpful source of information for you.</span><span style="font-family: Roboto;"> </span></p><p><span style="font-family: Roboto;">So, to start this new year (I know, it's already February) I want to share with you an updated review about therapies for achondroplasia that I prepared for <a href="https://www.blogger.com/#">Fundación Alpe</a> (Gijón, Spain). Alpe is one of the world's strongest advocacy groups for acondroplasia and skeletal dysplasias and you can find the original article translated to Spanish <a href="https://www.fundacionalpe.org/media/pdf/Kayserman%20castellano.pdf">here</a>. This review provides you with high level information about all drugs that are known to be (or could be) in clinical development for the treatment of achondroplasia. You can find more details about them here in the blog: you just need to search for them in the index page.<br /><br />Nevertheless, the research for therapies does not stop with the drugs listed in Table 1 below. New therapeutic approaches are being explored that we will be reviewing in the next blog's article.<br /></span></p><p><span style="font-family: Roboto;">Thank you for your interest in the Treating Achondroplasia blog!</span></p><p><span style="font-family: Roboto;"><br /><br /> <i><b>An update of the therapies for achondroplasia </b></i><br /></span><br /><span style="font-size: small;"><i><span style="font-family: Roboto;">Note: this review has been prepared originally for Fundación Alpe. </span></i></span><span style="font-family: Roboto;"><br /><br /></span></p><p><span style="font-family: Roboto;">Achondroplasia is the most common form of short-limbed dwarfism. This skeletal dysplasia is caused by a single point mutation in the <i>fibroblast growth factor receptor 3</i> (FGFR3) gene, which in turn encodes the protein FGFR3, which is located across the cell membrane of the chondrocytes (1). Upon binding of its ligands (the FGFs), it is activated and drives several important cell functions (Figure 1). <br /><br />FGFR3 has a key role in bone development by regulating the growth plate cartilage function. FGFR3 helps regulating bone growth by, like a brake in a car reducing its speed, counteracting the effect of many other agents which, as the car accelerator, promote bone growth (1). Without FGFR3, bones would elongate without control causing several medical complications (2). In achondroplasia, however, because of the mutation, FGFR3 is working a little too much thereby impairing bone growth (1). More potent mutations in FGFR3 lead to significantly more severe, sometimes lethal forms of skeletal dysplasia. <br /><br />The consequences of the FGFR3 mutation are well known and go beyond the short stature typical of achondroplasia. Sudden death and neurological problems in early infancy, sleep apnea, recurrent ear infections and multiple orthopedic complications among others throughout life, not to mention significant impact on the quality-of-life, have been already extensively documented in many studies (3,4). <br /><br />Since the mutation was discovered much has been learned about how it causes achondroplasia. Scientists started thinking and investigating how to control or reduce the activity of FGFR3 to help restoring bone growth. For instance, one of the first objective attempts to target FGFR3 for the treatment of achondroplasia was explored by the group led by Dr. Avner Yayon, who developed an antibody that could block FGFR3 and its activation (5). Unfortunately, FGFR3 works, as we saw above, in the growth plate cartilage, a very special tissue located within the very ends of each of our bones. The growth plate cartilage is a dense tissue that does not receive direct blood supply and these singular features prevent large molecules to transit inside it. As antibodies are very large molecules, in contrast to their vast use in treating many other diseases and in particular cancer, they couldn’t reach their target (FGFR3) in the growth plate, making them inappropriate for the treatment of achondroplasia. <br /><br />Nevertheless, as scientists were mapping the chemical reactions driven by or affecting FGFR3 (Figure 1), they learned about many other bone growth-promoting agents, too. For instance, they learned that the C-type natriuretic peptide (CNP) pathway plays a key role in bone growth and that it also antagonizes FGFR3 in growth plate chondrocytes. Increasing CNP levels in the growth plate restores, at least partially, bone growth (6,7). With this knowledge in hands, vosoritide has been developed (8), followed by TransCon-CNP (9). <br /><br />Figure 1. Pharmacological strategies targeting the FGFR3 pathway in the chondrocytes. <br /><br /></span></p><p style="text-align: center;"><span style="font-family: Roboto;"><a href="https://www.blogger.com/#"><img border="0" src="https://blogger.googleusercontent.com/img/a/AVvXsEg5dzBtdUZYrOYhUWSvIWWbMAV06qiupLUmS8xduf4a6TptB1MsW3vHcEbKt5yoZVEHMSFFuZ2J8CxSml_QDRUkf_YCyVm6t73XvOit7xVBQxFgLvg0dSO1H_TEGcVJDMSxHwfaJ6u8spNTEnimQj2lHgJ0AEnfJUyu0PsSubaar4ZhP9Rw5kkrzI10=w518-h640" /></a> </span></p><p style="text-align: center;"><span style="font-family: Roboto;"><span style="font-size: x-small;">Modified from Matsushita M et al. 2013 (10). Reproduced here for educational purposes only.</span><br /></span></p><p><span style="font-family: Roboto;"><br /> <br /> As FGFR3 may play important roles in some types of cancer, scientists have tried to block it with molecules called tyrosine kinase inhibitors (TKIs) which have the ability to “turn it off” or deactivate it. It was natural to think that a TKI could be explored in achondroplasia. Actually, two of them are in development for achondroplasia (see below) and others might follow the clinical development path (Figure 1). <br /><br />Scientists also paid attention in how FGFR3 is activated and if it was possible to prevent it. This resulted in the design of molecules like recifercept, a modified FGFR3 molecule that can circulate free, capturing the activators (FGFs) before they reach out to the genuine FGFR3. Using the same strategy, another molecule called aptamer was designed to do the same job, blocking one of the key FGFs before they turn on FGFR3 (Figure 1). <br /><br />You can find a list of the pharmacological agents being explored for the treatment of achondroplasia on Table 1 and more details about them below. <br /> <br /><br />Table 1. List of current and potential therapies for achondroplasia.</span></p><div align="center">
<table border="0" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="border-collapse: collapse; mso-padding-alt: 0mm 0mm 0mm 0mm; mso-yfti-tbllook: 1056; width: 632px;">
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<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: white;">Name</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #4f81bd; background-image: none; background-position: 0% 0%; background: rgb(79, 129, 189) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 3.0pt; border-color: white white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: solid solid solid none; border-top-color: white; border-top: solid white 1.0pt; border-width: 1pt 1pt 3pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: white;">Type</span></span></span></span></span></p>
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<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: white;">Developer</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #4f81bd; background-image: none; background-position: 0% 0%; background: rgb(79, 129, 189) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 3.0pt; border-color: white white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: solid solid solid none; border-top-color: white; border-top: solid white 1.0pt; border-width: 1pt 1pt 3pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: white;">RoA</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #4f81bd; background-image: none; background-position: 0% 0%; background: rgb(79, 129, 189) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 3.0pt; border-color: white white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: solid solid solid none; border-top-color: white; border-top: solid white 1.0pt; border-width: 1pt 1pt 3pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: white;">Frequency</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #4f81bd; background-image: none; background-position: 0% 0%; background: rgb(79, 129, 189) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 3.0pt; border-color: white white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: solid solid solid none; border-top-color: white; border-top: solid white 1.0pt; border-width: 1pt 1pt 3pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: white;">Status</span></span></span></span></span></p>
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<tr style="height: 17.8pt; mso-yfti-irow: 1;">
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 17.8pt; mso-border-top-alt: solid white 3.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Vosoritide</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 3.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">CNP analog</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 3.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Biomarin</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 3.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">SC</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 3.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">daily</span></span></span></span></span></p>
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<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 3.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Approved</span></span></span></span></span></p>
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<tr style="height: 17.8pt; mso-yfti-irow: 2;">
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 17.8pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">TransCon-CNP</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">CNP analog</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Ascendis</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">SC</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">weekly</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Phase 2</span></span></span></span></span></p>
</td>
</tr>
<tr style="height: 17.8pt; mso-yfti-irow: 3;">
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 17.8pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Infigratinib</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">TKI</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">QED</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">oral</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">daily</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Phase 2</span></span></span></span></span></p>
</td>
</tr>
<tr style="height: 17.8pt; mso-yfti-irow: 4;">
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 17.8pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Recifercept</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Ligand trap</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Pfizer</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">SC</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">daily</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Phase 2</span></span></span></span></span></p>
</td>
</tr>
<tr style="height: 17.8pt; mso-yfti-irow: 5;">
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 17.8pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Meclizine</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Anti-histaminic</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Nagoya University</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">oral</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">daily</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Phase 1</span></span></span></span></span></p>
</td>
</tr>
<tr style="height: 24pt; mso-yfti-irow: 6;">
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 24pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">RBM-007</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 24pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">FGF2 Aptamer</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 24pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Ribomic</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 24pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">SC</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 24pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">NA</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 24pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Phase 1</span></span></span></span></span></p>
</td>
</tr>
<tr style="height: 17.8pt; mso-yfti-irow: 7;">
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-top: none; border: 1pt solid white; height: 17.8pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 93.15pt;" valign="top" width="124">
<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><a name="_Hlk94522139"><span style="color: black;">SAR442501</span></a></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Antibody</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Sanofi</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">IV(?)</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">NA</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Phase 1</span></span></span></span></span></p>
</td>
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<tr style="height: 17.8pt; mso-yfti-irow: 8;">
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<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">ASP-5878</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">TKI</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 91.5pt;" valign="top" width="122">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Astellas</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">NA</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">NA</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #d0d8e8; background-image: none; background-position: 0% 0%; background: rgb(208, 216, 232) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Pre-clinical</span></span></span></span></span></p>
</td>
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<tr style="height: 17.8pt; mso-yfti-irow: 9; mso-yfti-lastrow: yes;">
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<p class="MsoNormal"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">ASB-20123</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 92.2pt;" valign="top" width="123">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">CNP analog</span></span></span></span></span></p>
</td>
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<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Daichii-Sankio</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 46.1pt;" valign="top" width="61">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">NA</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 74.45pt;" valign="top" width="99">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">NA</span></span></span></span></span></p>
</td>
<td style="background-attachment: scroll; background-color: #e9edf4; background-image: none; background-position: 0% 0%; background: rgb(233, 237, 244) none repeat scroll 0% 0%; border-bottom-color: white; border-bottom: solid white 1.0pt; border-color: currentcolor white white currentcolor; border-left: none; border-right-color: white; border-right: solid white 1.0pt; border-style: none solid solid none; border-top: none; border-width: medium 1pt 1pt medium; height: 17.8pt; mso-border-left-alt: solid white 1.0pt; mso-border-top-alt: solid white 1.0pt; padding: 3.6pt 7.2pt; width: 76.35pt;" valign="top" width="102">
<p align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: small;"><span style="font-family: Roboto;"><span><span><span style="color: black;">Pre-clinical</span></span></span></span></span></p>
</td>
</tr>
</tbody></table>
</div><span style="font-family: verdana;">
</span><p><span style="font-family: verdana;"><i><span style="color: white; font-size: 11pt;">CNP: C-type natriuretic
peptide. RoA: route of administration. SC: subcutaneous. TKI: </span></i></span><span style="font-family: Roboto;"><br /><i><b><br />Vosoritide</b></i> <br /><br />After long years of clinical development culminating with a successful phase 3 study (11), vosoritide, branded as Voxzogo, has been approved for the treatment of achondroplasia in 2021. In Europe (EMA countries) and Brazil, vosoritide has been approved for children two years of age and older while, in the US, the Food and Drug Administration (FDA) authorized the treatment for children from five years old onward. Other countries will soon follow suit. <br /><br />Beyond the phase 2 and 3 studies in older children, Biomarin is also testing vosoritide in other three clinical trials, one in infants (<a href="https://www.blogger.com/#">NCT03583697</a>), one in children with achondroplasia at higher risk of clinical complications (<a href="https://www.blogger.com/#">NCT04554940</a>) and also in a study with other selected forms of genetic growth disorders (<a href="https://www.blogger.com/#">NCT04219007</a>). </span></p><p><span style="font-family: Roboto;"><br /><br /><i><b>TransCon-CNP </b></i><br /><br />The main difference between TransCon-CNP and vosoritide is that TransCon-CNP is delivered through a slow-release system allowing a weekly dose with sustained exposure to their analog in contrast with vosoritide's daily dosing. In pre-clinical studies they showed that their CNP analog was superior to vosoritide (9). <br /><br />Ascendis Pharma is conducting the phase 2 study <a href="https://www.blogger.com/#">ACcomplisH </a>with TransCon-CNP. During the JPMorgan 2022 Healthcare Conference in early January (Figure 2), they reported that TransCon-CNP has been well tolerated during the study, with already 65 weeks of drug exposure. They plan to release the data from the phase 2 study in the end of 2022. <br /><br />Figure 2. ACcomplisH study design (from Ascendis’ JPMorgan 2022 Healthcare Conference presentation). <br /><br /><br /><a href="https://www.blogger.com/#"><img border="0" src="https://blogger.googleusercontent.com/img/a/AVvXsEh2QrLihTxoLXGrAnb1PpcSc5D8BL7ypF2V6wOOHPkGnECsYGpXeWOBdAv7KNTapvTvrHSkqdfU8b3Ci7lXWZZoKZyA-2JSjnG394t4ZC1Ns5RgDASK8jpLqyxCmQkSyAkTf2Z0ZvUnVetgA26ukBS6fK5dLz2Vt85oovxYUFjlZXjpNwkx66Rgu-VP=w640-h358" /></a><br /><br /><br /><br /> <br /><br /><i><b>Infigratinib</b></i> <br /><br />Infigratinib is an oral molecule initially developed to treat several types of cancer where FGFRs play an important role for the progression of the disease. It works by blocking the FGFRs' signaling cascades inside the cell (Figure 1). Given that an abnormal, overactive FGFR3 is the cause of achondroplasia, investigators sought to find whether infigratinib could be used to treat this skeletal dysplasia. Preclinical studies demonstrated that it rescued bone growth in a mouse model of achondroplasia, in doses much lower than those used in the first studies in cancer (12,13). <br /><br />QED, a BridgeBio arm, has been conducting the phase 2 trial called <a href="https://www.blogger.com/#">PROPEL</a> and, according to their presentation during the JPMorgan 2022 Healthcare Conference, infigratinib has been showing a safe profile. They estimate to have results from the study by the end of the second quarter this year (Figure 3). Depending on the results they plan to open the phase 3 study right in 2023. <br /><br />Figure 3. Phase 2 study PROPEL design (from the BridgeBio’s JPMorgan 2022 Healthcare Conference presentation). <br /><br /><br /><a href="https://www.blogger.com/#"><img border="0" src="https://blogger.googleusercontent.com/img/a/AVvXsEj4DGRN3qDTabsOML9hBMY06IGSH-_1sI57ILSBylDWmS4cWZGiPzJ4m2pOG9kSGEdgqs8zv124-cjt_m1Sl0qvHRUEGP4wj5Fa1uhPIfIUqjdCDm26VwQWl_jMPi-cYbWSnG-ZndMVcbd6k2b-bBNUIpWL0YwGGsEm2M9drlmudNUcu5qSJ0yftLT2=w640-h360" /></a><br /><br /><br /><br /> <br /><br /><i><b>Recifercept</b></i> <br /><br />Recifercept is a modified, free form of FGFR3 that works as a "ligand trap", capturing FGFR activators (ligands: the FGFs) before they can bind and activate these receptors, including FGFR3. Without the activators FGFR3 would not be as active as expected and this would help restoring bone growth (14,15). <br /><br />Pfizer has started a <a href="https://www.blogger.com/#">phase 2 study</a> with recifercept in the end of 2020 but there have been no significant updates since then. </span></p><p><span style="font-family: Roboto;"><br /><br /><i><b>Meclizine</b></i> <br /><br />Drug repurposing is a strategy where investigators try to find new therapeutic indications for old drugs. The concept is that its development for the new purpose should be much less expensive and the final drug cost, if approved, would be surely more affordable than the cost of newly created compounds. Meclizine is an old drug that has been used to treat motion sickness for decades. In an effort to find potential treatments for achondroplasia the Japanese group from University of Nagoya leaded by Dr. Kitoh has found that meclizine was able to inhibit the FGFR3 function and to partially rescue bone growth in their animal model (10,16). They have subsequently conducted a phase 1 study in children with achondroplasia (17). The study showed that meclizine could be suitable for a single daily dose (but that it would need to be further explored in subsequent studies). More recently, they conducted <a href="https://www.blogger.com/#">another study</a> to evaluate multiple doses of meclizine for a period of two weeks, but no results have been published yet. <br /><br /> <br /><br /><i><b>RBM-007 </b></i><br /><br />Ribomic has been developing RBM-007, an anti-FGF2 aptamer designed to treat conditions where FGF2 has a relevant role in the mechanism of disease (18). Since FGF2 is considered a key activator (ligand) of FGFR3 and that in achondroplasia FGFR3 is overactive, then if it was less activated by FGF2 perhaps bone growth could be restored. <br /><br />Ribomic published their pre-clinical studies with RBM-007, which indeed rescued bone growth in a model of achondroplasia (19). They have already started a <a href="https://www.blogger.com/#">phase 1 clinical trial</a> to evaluate this aptamer for achondroplasia and are planning to start a phase 2 study in children with achondroplasia during 2022 (Figure 4). <br /><br />Figure 4. Clinical development plan of RBM-007 for achondroplasia (from Ribomic’s JPMorgan 2022 Healthcare Conference presentation). <br /><br /><br /><a href="https://www.blogger.com/#"><img border="0" src="https://blogger.googleusercontent.com/img/a/AVvXsEjGrJ4pMobHwoFntGtiluVN3fkT3hvuMJFqeikn7l9XWorBeW0k2ugxJzcyrNRfuIqsPAx0qfCjrzktS3XuRrTpraZ47o3BfNllJJNr9PgDa9I-vwzxAOO5yRl95wM05_PHtN6JTlXj0rw6cbZ1HlFCc-4y1ApHj-RHDGELrxokGb_LJx85xS2jqUSd=w640-h360" /></a><br /><br /><br /><br /> <br /><i><b>SAR442501</b></i> <br /><br />Last year, Sanofi announced that SAR442501, an anti-FGFR3 antibody, was transitioned to Phase 1 clinical development. However, no study information could be found on the European Clinical Trial Register, on ClinicalTrials.gov, or the Australian Clinical Trial Register. Apart from being listed in the Sanofi’s <a href="https://www.blogger.com/#">pipeline website</a> and in their Feb 2021 <a href="https://www.blogger.com/#">financial report</a> (and other reports in their website), no further information about the development of SAR442501 could be found there. Neither pre-clinical data could be found in the Pubmed portal nor through a Google search as of 31-Jan-2022. <br /><br />Although the antibody strategy is attractive due to its high specificity, the ability of a specific antibody to target FGFR3 in the growth plate in a model of achondroplasia needs to be confirmed in an appropriate model. As mentioned above, the growth plate is a unique body tissue because it lacks direct blood supply. Nutrients and oxygen must traffic through a dense matrix which involves the chondrocytes. In this setting, large molecules such as antibodies might not be able to reach out to chondrocytes to exert their effects (20). <br /><br />SAR442501 is not the first antibody against FGFR3 to be developed (6). Until recently, B-701 (R3Mab) (21), also known as votafamab, was being developed for cancer and potentially for achondroplasia, but it seems that the research for this indication has been abandoned as there have been no reports about this antibody for this indication for a long time. </span></p><p><span style="font-family: Roboto;"><br /><br /><b><i>ASP-5878 </i></b><br /><br />Astellas Pharma has recently published a study where they explored the use of ASP-5878, a TKI similar to infigratinib, in pre-clinical models to treat achondroplasia (22). They found that the drug was able to improve bone growth, however it was less effective compared to a positive control, a CNP analog bearing the same structure of vosoritide. </span></p><p><span style="font-family: Roboto;"><br /><i><b><br /> ASB-20123 </b></i><br /><br />Asubio, a Japanese biotech that was recently incorporated by Daichii-Sankio (DS), was developing another CNP analog based on the fusion of the active fragment of CNP and a backbone fragment of the hormone ghrelin to help extending the known short CNP’s half-life. They have published some studies showing that their molecule was able to improve bone growth in pre-clinical models (23) but there has been no news about this compound in the DS website or in the literature lately.<br /> <br /> <br /><i><b>A new era started </b></i><br /><br />With the approval of vosoritide, a new era started. Treating achondroplasia goes far beyond simply improving the final individual height, which nevertheless is an important objective. Although long term data about the effects of vosoritide (and of course the others, too) is not available yet, based on current evidence, there is a fair chance that these therapies may mitigate or prevent several clinical challenges children with achondroplasia face in their daily routine, as mentioned in the beginning of this review. <br /><br />These children now may have access to a therapy that might help them develop better and have the same opportunities and challenges an average child has while they grow into adulthood. Neither more nor less. I think this is a good perspective. </span></p><p><span style="font-family: Roboto;"><br /><br /><i><b>References </b></i><br /><br />1. <a href="https://www.blogger.com/#">Horton WA et al</a>. Achondroplasia. Lancet 2007; 370: 162–72. <br /><br />2. <a href="https://www.blogger.com/#">Toydemir RM et al</a>. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet 2006;79(5):935-41. Open access. <br /><br />3. <a href="https://www.blogger.com/#">Savarirayan R et al</a>. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat Rev Endocrinol 2021 Nov 26. Open access. <br /><br />4. <a href="https://www.blogger.com/#">Hoover-Fong J</a> et al. Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history. Bone. 2021 May;146:115872. Open access. <br /><br />5. <a href="https://www.blogger.com/#">Aviezer D et al</a>. Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism. Curr Drug Targets 2003 Jul;4(5):353-65. <br /><br />6. <a href="https://www.blogger.com/#">Golembo M and Yayon A</a>. <a href="https://www.blogger.com/#">Method and composition for treatment of skeletal dysplasias</a>. US patent 20040138134. September 2003. Open access. <br /><br />7. <a href="https://www.blogger.com/#">Yasoda A, Nakao K</a>. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocr J 2010;57(8):659-66. Open access. <br /><br />8. <a href="https://www.blogger.com/#">Lorget F et al</a>. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 2012 Dec 7;91(6):1108-14. Open access. <br /><br />9. <a href="https://www.blogger.com/#">Breinholt VM et al</a>. TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias. J Pharmacol Exp Ther 2019; 370(3): 459-71. Open access. <br /><br />10. <a href="https://www.blogger.com/#">Matsushita M et al</a>. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One 2013 Dec 4;8(12): e81569. doi: 10.1371/journal.pone.0081569. Open access. <br /><br />11.<a href="https://www.blogger.com/#"> Savarirayan R et al</a>. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; 396 (10257):1070. <br /><br />12. <a href="https://www.blogger.com/#">Komla-Ebri D et al</a>. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016; 126(5):1871-84. Open access. <br /><br />13. <a href="https://www.blogger.com/#">Demuynck B et al</a>. Support for a new therapeutic approach of using a low-dose FGFR tyrosine kinase inhibitor (infigratinib) for achondroplasia. Approved by but not presented at ENDO 2020 due to COVID-19 pandemics. Accessed on 01-Jan-2022. Open access. <br /><br />14.<a href="https://www.blogger.com/#"> Garcia S et al</a>. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 2013; 5 (203):203ra124. Open access after registration. <br /><br />15. <a href="https://www.blogger.com/#">Gonçalves D et al</a>. In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia. PLoS ONE 2020; 15(12): e0244368. Open access. <br /><br />16. <a href="https://www.blogger.com/#">Matsushita M et al</a>. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene. Endocrinology 2015; 156(2):548-54. Open access. <br /><br />17. <a href="https://www.blogger.com/#">Kitoh H</a><a href="https://www.blogger.com/#"> et al</a>. Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia. PLoS ONE 2020;15(4): e0229639. Open access. <br /><br />18. <a href="https://www.blogger.com/#">Ling Jin et al.</a> Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain. Mol Ther 2016; 24 (11): 1974-1986. Open access. <br /><br /> 19. <a href="https://www.blogger.com/#">Kimura T et al</a>. An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice. Sci Transl Med 2021 May 5;13(592): eaba4226. <br /><br />20. <a href="https://www.blogger.com/#">Farnum CE et al</a>. In vivo delivery of fluoresceinated dextrans to the murine growth plate: imaging of three vascular routes by multiphoton microscopy. Anat Rec A Discov Mol Cell Evol Biol 2006 Jan;288(1):91-103. Open access. <br /><br />21<a href="https://www.blogger.com/#">. Qing J et al</a>. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest 2009 May;119(5):1216-29. Open access. <br /><br />22. <a href="https://www.blogger.com/#">Ozaki T et al</a>. Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia. Sci Rep 2020; 10: 20915. Open access. <br /><br />23. <a href="https://www.blogger.com/#">Morozumi N et al</a>. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoSONE 2019;14(2): e0212680. Open access. <br /><br /> </span></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com2tag:blogger.com,1999:blog-4791085249231790709.post-46373992288290686582021-11-11T11:37:00.004-05:002021-11-16T14:19:39.760-05:00 Tratando a acondroplasia: do sonho à realidade<p><span style="font-family: verdana;"> <i><b>O futuro bate à porta</b></i></span></p><p><span style="font-family: verdana;">Estamos agora a menos de duas semanas do dia do PDUFA* do Voxzogo, quando a <i>Food and Drug Administration</i> (FDA) irá liberar sua resposta ao pedido de comercialização do vosoritide. O vosoritide está em desenvolvimento clínico há cerca de dez anos, sendo investigado como uma terapia para a acondroplasia, a forma mais comum de nanismo. Essa longa estrada tem sido percorrida em meio a vários obstáculos e solavancos ao longo do caminho e, agora que a droga já foi aprovada na Europa, as expectativas são todas sobre como e se a decisão do FDA realmente abrirá novas portas para famílias interessadas em melhorar a saúde de seus filhos com acondroplasia. Mas, vamos ver do que se tratam essas expectativas, já que a próxima semana pode trazer surpresas. </span></p><p><span style="font-family: verdana;">Como os 17 leitores deste blog certamente sabem, a acondroplasia é causada por uma mutação no gene que codifica uma enzima chamada receptor do fator de crescimento de fibroblastos 3 (FGFR3). Eu sei, eu sei, corro o risco de ficar um pouco repetitivo, mas acho que a volta que farei aqui pode nos ajudar a entender o que podemos esperar do dia PDUFA do vosoritide. </span></p><p><i><b><span style="font-family: verdana;">Causas e consequências</span></b></i></p><p><span style="font-family: verdana;"></span></p><p><span style="font-family: verdana;">O FGFR3, junto com muitas outras enzimas, desempenha um papel fundamental durante a fase que os cientistas chamam de <i>desenvolvimento</i>. O desenvolvimento começa com o ovo fertilizado e vai até o final da puberdade e é composto por processos biológicos fortemente regulados por centenas de enzimas como o FGFR3. Você pode chamar esses processos de <i>procedimentos operacionais padrão</i> (POPs). Essas enzimas trabalham em conjunto para fazer com que os POPs funcionem sem problemas, mas quando uma delas sofre mudanças (mutação), seja para funcionar mais do que o planejado ou simplesmente para de funcionar, o processo de desenvolvimento é perturbado. </span></p><p><span style="font-family: verdana;">O FGFR3 é particularmente importante no desenvolvimento ósseo porque atua reduzindo o ritmo de crescimento ósseo, modulando os estímulos de crescimento produzidos por várias outras enzimas. Em um carro, enquanto essas outras enzimas funcionariam como um acelerador, o FGFR3 é um freio. Se não houvesse FGFR3, os ossos cresceriam sem controle e causariam vários problemas médicos. Na verdade, as mutações no FGFR3 que o inativam causam uma síndrome de supercrescimento conhecida como síndrome CATSHL (camptodactilia, estatura alta, escoliose e perda auditiva). (1) <br /></span></p><p><span style="font-family: verdana;">O freio é importante em um carro para que sua velocidade seja controlada. No entanto, a mutação no FGFR3 que causa a acondroplasia faz com que ele funcione demais, de modo que o carro mal consegue se mover (o freio domina o acelerador). O resultado é que, na acondroplasia, os ossos, especialmente os ossos longos e as vértebras, crescem apenas uma fração do que deveriam, em contraste com todos os outros tecidos do corpo. </span></p><p><span style="font-family: verdana;">Indivíduos com acondroplasia têm baixa estatura adulta, mas esta não é a única característica relevante, uma vez que o crescimento esquelético restrito tem importantes consequências além da altura. O desequilíbrio entre os ossos mais curtos ou estreitos em comparação com todos os outros tecidos normais frequentemente leva à complicações clínicas que estão listadas nas diretrizes publicadas sobre a acondroplasia. </span></p><p><span style="font-family: verdana;">Devido ao comprometimento do crescimento ósseo, em média os indivíduos com acondroplasia requerem mais utilização de cuidados de saúde, incluindo tratamento cirúrgico para complicações ortopédicas e neurológicas comuns (por exemplo: estenose do forame magno, estenose espinhal, problemas nas articulações etc.), entre outras, enquanto os adultos também são propensos à obesidade, maior incidência de doenças cardíacas e menor expectativa de vida em relação à população em geral. (2) </span></p><p><span style="font-family: verdana;">À medida que o conhecimento sobre a história natural da acondroplasia é aprofundado, fica claro que se trata de uma desordem genética que afeta muito mais do que a altura final. </span></p><p><i><b><span style="font-family: verdana;">Desenvolvendo a primeira terapia para acondroplasia</span></b></i></p><p><span style="font-family: verdana;">A alteração genética que leva à acondroplasia foi identificada há quase 30 anos (3-5), mas apenas mais recentemente esforços foram direcionados para encontrar maneiras de corrigir o defeito de crescimento ósseo causado pela mutação </span><span style="font-family: verdana;">hiperativa</span><span style="font-family: verdana;"> do FGFR3. Isso se tornou possível porque as redes químicas reguladas pelo FGFR3 foram identificadas (Figura 1), bem como a maioria das vias conduzidas por outros agentes envolvidos no desenvolvimento e crescimento ósseo. Isso, por sua vez, permitiu aos cientistas descobrir quais dessas vias são afetadas por mutações no FGFR3. (6) </span></p><p><span style="font-family: verdana;">Figura 1. Vias de sinalização relevantes do FGFR3 no condrócito.</span></p><p><span style="font-family: verdana;"> </span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-TCJnxi7B-0_3w-7NBTcoK-4_HZPExvJRQ1iIXHofdXIWBdPwwrxEiOERmeMxeY9DqiT_Xla_En5e82NlrHbVw5sGsmHaS5cSijAD42DMrN5vvhAHq5Wi4FNNE5fBp20HlaREqR3qKjU/s602/FGFR3ModelNature.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="580" data-original-width="602" height="461" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-TCJnxi7B-0_3w-7NBTcoK-4_HZPExvJRQ1iIXHofdXIWBdPwwrxEiOERmeMxeY9DqiT_Xla_En5e82NlrHbVw5sGsmHaS5cSijAD42DMrN5vvhAHq5Wi4FNNE5fBp20HlaREqR3qKjU/w478-h461/FGFR3ModelNature.jpg" width="478" /></a></div><br /><p></p><p><span style="font-family: verdana;"></span></p><p><span style="font-family: verdana;">Um desses outros agentes de desenvolvimento ósseo é uma enzima chamada <i>receptor de peptídeo natriurético B</i> (NPR-B). Tanto o FGFR3 quanto o NPR-B estão localizados na membrana celular dos condrócitos, as células que governam o crescimento ósseo. Eles podem ser vistos como interruptores de luz nas paredes de nossa casa que são ligados e desligados quando os movemos para cima e para baixo. No corpo, o FGFR3 é ativado por FGFs enquanto o NPR-B é ativado pelo <i>peptídeo natriurético tipo C</i> (CNP). Os cientistas descobriram que o CNP é um agente de crescimento ósseo positivo que atua precisamente reduzindo a atividade do FGFR3 no condrócito. (Figura 2). Eles também viram que a via do FGFR3 pode inibir o eixo CNP + NPR-B. (7) </span></p><p><span style="font-family: verdana;">Figura 2. Cruzamento das vias de sinalização do FGFR3 e do NPR-B no condrócito.</span></p><p><span style="font-family: verdana;"> </span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjGLRSit8mMCDFcUIebT2tFQg3AaDbgNVhQU07yrt618aFmt-g73oguFNl7vcFVu5b8IngkM7nDTZhg_MI1_2a-kVIN2kM7jw32eFkI_D8m5DPtLnBg_Yv3EgCfcNmtfSERWvF7_BJswtU/s557/william-horton+FGFR3_CNP+crosstalk.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="409" data-original-width="557" height="389" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjGLRSit8mMCDFcUIebT2tFQg3AaDbgNVhQU07yrt618aFmt-g73oguFNl7vcFVu5b8IngkM7nDTZhg_MI1_2a-kVIN2kM7jw32eFkI_D8m5DPtLnBg_Yv3EgCfcNmtfSERWvF7_BJswtU/w529-h389/william-horton+FGFR3_CNP+crosstalk.jpg" width="529" /></a></div><br /><p></p><p><span style="font-family: verdana;"><br /> Tendo entendido que o CNP modula a atividade do FGFR3 e que pode estar funcionando menos do que o normal na acondroplasia, o próximo passo foi verificar se o fornecimento </span><span style="font-family: verdana;">suplementar </span><span style="font-family: verdana;">de CNP ajudaria a reduzir os efeitos do FGFR3 mutante. Na verdade, isso foi prontamente visto: a adição de CNP a culturas de células, explantes ósseos e modelos animais de acondroplasia restaurou, pelo menos parcialmente, o crescimento ósseo. (8) Uma primeira terapia potencial para a acondroplasia parecia estar disponível. </span></p><p><span style="font-family: verdana;">No entanto, um problema que os cientistas enfrentaram ao lidar com o CNP é que se trata de uma molécula frágil. Peptídeos como o CNP são muito ativos e devem permanecer sob controle. Quando no sangue o CNP dura menos de três minutos circulando, pois é um alvo fácil para os sistemas naturais de limpeza que possuímos. Então, como resolver esse problema? Eles aprenderam que outro peptídeo natriurético chamado BNP é naturalmente mais resistente ao sistema de limpeza porque tem uma estrutura ligeiramente diferente. Eles adaptaram o CNP para "parecer" com o BNP e essa mudança deu origem à invenção do vosoritide. (9) Portanto, vosoritide é uma versão modificada do CNP, também chamada de análogo. </span></p><p><span style="font-family: verdana;">O vosoritide dura cerca de 20 minutos no sangue, tempo suficiente para atingir as zonas de crescimento ósseo (as placas de crescimento) e exercer os seus efeitos. Então, quais são esses efeitos? Ao reduzir a atividade do FGFR3, o eixo NPR-B restaura a capacidade dos condrócitos de proliferar e aumentar (hipertrofiar), as quais são as duas etapas principais pelas quais eles precisam passar para fazer os ossos crescerem. (8) </span></p><p><span style="font-family: verdana;">Um grande desafio no início do desenvolvimento clínico do vosoritide deve ter sido como medir sua eficácia. Em humanos, o crescimento ósseo constitui um processo longo e lento, portanto as mudanças não são identificadas no dia a dia, mas só podem ser vistas quando dois pontos distantes no tempo são comparados. Esse desenvolvimento lento torna difícil estabelecer objetivos quando alguém está tentando corrigir uma perturbação no processo de crescimento ósseo. Ainda mais difícil seria confirmar se a melhora do crescimento ósseo com a droga experimental proporcionaria benefícios adicionais em termos de redução das complicações médicas frequentes que resultam de ossos curtos e estreitos, como a estenose espinhal. Então, como podemos medir esses efeitos? Após longas discussões, como podemos ver descritas nas muitas conferências públicas (principalmente aquelas conferências financeiras) ao longo dos anos, o parâmetro final acordado entre o desenvolvedor do vosoritide e os reguladores, que permitiria determinar se o vosoritide era benéfico (eficácia) no tratamento da acondroplasia foi a <i>velocidade de crescimento ósseo</i>. </span></p><p><span style="font-family: verdana;">O Vosoritide vem sendo testado em crianças com acondroplasia há anos e, de acordo com os dados já disponíveis, ajuda a restaurar o crescimento ósseo a um nível próximo do que acontece em uma criança normal. (10-12) Os dados apresentados à Agência Europeia de Medicamentos (EMA) foram analisados e, em agosto passado, o vosoritide foi aprovado para o tratamento da acondroplasia nos países europeus que trabalham com aquela agência. Os mesmos dados também foram submetidos à Food and Drug Administration (FDA), a qual divulgará seus comentários em alguns dias, como mencionei acima. </span></p><p><span style="font-family: verdana;"><i><b>O futuro está presente</b></i> </span></p><p><span style="font-family: verdana;">A aprovação do vosoritide na Europa é um marco para o tratamento da acondroplasia e muito provavelmente para muitas outras displasias esqueléticas em que o crescimento ósseo é prejudicado. Uma característica importante do eixo CNP + NPR-B é que ele funciona independentemente do FGFR3. O uso de análogos do CNP como o vosoritide (há outros em desenvolvimento) pode ajudar a melhorar o crescimento ósseo nessas outras doenças genéticas, não apenas melhorando a altura, mas também as complicações médicas relacionadas a outras condições de restrição de crescimento, como esperamos ver na acondroplasia. </span></p><p><span style="font-family: verdana;">Pode levar mais alguns anos para ver se as crianças tratadas com vosoritide sofrerão menos complicações, tais como infecções do ouvido médio, apnéia do sono, estenose espinhal e genu varum, do que o que é frequentemente visto hoje, mas as expectativas de longo prazo sobre esses benefícios potenciais não devem levar à conclusão de que este medicamento, e todos os outros candidatos que virão, não ajudariam a reduzir essas complicações. E por que isso? Simplesmente porque o tratamento é sistêmico, ou seja, o medicamento chega a todos os ossos ao mesmo tempo. Não há lógica em pensar que apenas um tipo de osso seria afetado pelo tratamento. Portanto, o tratamento não deve apenas aumentar o comprimento dos ossos longos, mas também deve ajudar a alargar outros ossos, como as vértebras, que também crescem através das placas de crescimento. </span></p><p><span style="font-family: verdana;"><i><b>Saúde infantil</b></i> </span></p><p><span style="font-family: verdana;">Aqui está a definição de saúde da Organização Mundial de Saúde: </span></p><ul style="text-align: left;"><li><span style="font-family: verdana;">Saúde é um estado de completo bem-estar físico, mental e social e não apenas a ausência de doença ou enfermidade. </span></li></ul><p><span style="font-family: verdana;">O acúmulo de evidências sobre a história natural da acondroplasia mostra que crianças e adultos com essa displasia esquelética sofrem impactos não apenas no aspecto físico, mas também nos campos mental (emocional) e de bem-estar social. (13,14). S</span><span style="font-family: verdana;"><span class="VIiyi" lang="pt"><span class="JLqJ4b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span>erá positivo ver como os tratamentos farmacológicos para a acondroplasia afetarão esses aspectos da saúde. </span></span></span></span></p><p><span style="font-family: verdana;"><span class="VIiyi" lang="pt"><span class="JLqJ4b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span>Com base nas evidências publicadas, os indivíduos submetidos a alongamento cirúrgico de membros apresentam melhora do índice de qualidade de vida após a cirurgia (15, 16), o que implica que a melhora da altura foi benéfica para os outros aspectos da saúde destacados na definição da OMS. Quando pensamos sobre essa melhora observada após a cirurgia de alongamento precisamos lembrar que a cirurgia apenas aumenta a altura, não tendo efeito nas outras características da acondroplasia e em suas complicações comuns, ao contrário do que se espera com as terapias farmacológicas. </span></span></span></span></p><p><span style="font-family: verdana;"><span class="VIiyi" lang="pt"><span class="JLqJ4b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span>Podemos prever um tempo em que bebês e crianças pequenas com acondroplasia não precisarão de ressonâncias magnéticas para descartar estenose do forame magno, ou que crianças não precisarão mais comparecer a consultas repetidas a um otorrinolaringologista para inserir tubos de ouvido, ou que não serão submetidas à amigdalectomia para melhorar sua apnéia do sono, apenas para citar umas poucas situações estressantes pelas quais frequentemente passam ainda tão pequenas. Eles também poderão ser capazes de fazer qualquer coisa que uma criança comum faz, sem os desafios comuns que enfrentam hoje devido ao seu crescimento restrito. </span></span></span></span></p><p><span style="font-family: verdana;"><span class="VIiyi" lang="pt"><span class="JLqJ4b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span>Em conclusão, com base nas evidências atuais, acredito que, com a melhora do crescimento ósseo, as crianças com acondroplasia em tratamento com vosoritide e, no futuro, com outras terapias potenciais, alcançarão benefícios que vão além da redução do risco de complicações médicas, mas certamente à melhoria nos aspectos mentais e sociais, também. Esses benefícios potenciais devem ser levados em conta pelas partes interessadas (autoridades de saúde, planos de saúde, seguradoras) que serão responsáveis por responder a pergunta quanto a adotar ou não terapias para a acondroplasia. Para mim, a resposta simples a essa pergunta é <b>sim</b>. </span></span></span></span></p><p><span style="font-family: verdana;"><i><b><span class="VIiyi" lang="pt"><span class="JLqJ4b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span> </span></span></span></b></i></span></p><p><span style="font-family: verdana;"><i><b><span class="VIiyi" lang="pt"><span class="JLqJ4b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span>Referências</span></span></span></b></i> </span><br /><span style="font-family: verdana;"></span></p><p><span style="font-family: verdana;"></span><br /><span style="font-family: verdana;"><span class="VIiyi" lang="pt"><span class="JLqJ4b ChMk0b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span>* Da Wikipedia: Data PDUFA: Na prática regulatória farmacêutica dos Estados Unidos, a data PDUFA é o nome coloquial para a data em que a Food and Drug Administration deve responder a um pedido de novo medicamento ou licença biológica.</span></span></span></span></p><p><span style="font-family: verdana;"><span class="VIiyi" lang="pt"><span class="JLqJ4b ChMk0b" data-language-for-alternatives="pt" data-language-to-translate-into="en" data-number-of-phrases="1" data-phrase-index="0"><span> </span></span></span><br />1. <a href="https://www.sciencedirect.com/science/article/pii/S0002929707608362/pdfft?md5=74246b7164bc40c0a835de99c9c0e575&pid=1-s2.0-S0002929707608362-main.pdf">Toydemir RM</a>, Brassington AE, Bayrak-Toydemir P et al. Novel mutation in FGFR3 causes Camptodactyly, Tall Stature, and Hearing Loss (CATSHL) Syndrome. AGHG 2006; 79 (5): 935-41. Free access.<br /><br />2. <a href="https://doi.org/10.1542/peds.2020-1010">Hoover-Fong J</a>, Scott CI, Jones MC et al. Health supervision for people with achondroplasia. Pediatrics 2020 Jun;145(6):e20201010. Free access.<br /><br />3. <a href="https://idp.nature.com/authorize/casa?redirect_uri=https://www.nature.com/articles/371252a0.pdf%3Forigin%3Dppub&casa_token=CagN5vd-8yMAAAAA:fU7SLsofnSV1NKdNNkQ4_8anxGww5UGBC3vDhkP_USnr4w8gYvC79_gvt9FnW_oHnSDOz6snydh6Wm95Pg">Rousseau F,</a> Bonaventure J, Legeai-Mallet L et al., Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994; 371 (6494); 252–54. Free access.<br /><br />4. <a href="https://pubmed.ncbi.nlm.nih.gov/7913883/">Shiang R</a>, Thompson LM, Zhu YZ et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78 (2): 335–42.<br /><br />5. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1801129/pdf/ajhg00028-0015.pdf">Bellus GA</a>, Hefferon TW, Ortiz de Luna R et al. Achondroplasia is defined by recurrent G380R<br />mutations of FGFR3. Am J Hum Genet 1995; 56:368-73. Free access.<br /><br />6. <a href="https://doi.org/10.1016/j.bone.2020.115579">Legeai-Mallet L</a> and Savarirayan R. Novel therapeutic approaches for the treatment of achondroplasia. Bone 2020; 141:115579. Free access.<br /><br />7. <a href="https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/144484/1/yigak02905.pdf">Ozasa A</a>, Y. Komatsu A. Yasoda M et al. Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 2005; 36: 1056-64. Free access. <br /><br />8. <a href="https://doi.org/10.1016/j.ajhg.2012.10.014">Lorget F</a>, Kaci N, Peng J et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia Am J Med Gen 2012; 91(6):1108-14. Free access. 9. <a href="https://doi.org/10.1124/jpet.114.218560">Wendt DJ</a>, Dvorak-Ewell M, Bullens S et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 2015;353(1):132-49. <br /> <br /> 10. <a href="https://pubmed.ncbi.nlm.nih.gov/31269546/"> </a> <a href="https://www.nejm.org/doi/pdf/10.1056/NEJMoa1813446?articleTools=true">Savarirayan R</a>, Irving M, Bacino CA et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med 2019; 381(1):25-35. Free access.<br /> <br />11. <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31541-5/fulltext">Savarirayan R</a>, Tofts L, Irving M. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; 396(10252):684-692. Free access.<br /><br />12. <a href="https://doi.org/10.1038/s41436-021-01287-7">Savarirayan R</a>, Tofts L, Irving M. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med 2021 Aug 2;1-5. doi: 10.1038/s41436-021-01287-7. Free access.<br /><br />13. <a href="https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1171-9">Witt S</a>, Kolb B, Bloemeke J et al. Quality of life of children with achondroplasia and their parents - a German cross-sectional study. Orphan J Rare Dis 2019;14(1):194. Free access. <br /><br />14. <a href="https://pubmed.ncbi.nlm.nih.gov/33369042/">Yonko EA</a>, Emanuel JS, Carter EM et al. Quality of life in adults with achondroplasia in the United States. Am J Med Gen 2021; 185(3):695-701.<br /><br />15. <a href="https://doi.org/10.3109/17453670903473024">Moraal JM</a>, Elzinga-Plomp A, Jongmans MA et al. Long-term psychosocial functioning after Ilizarov limb lengthening during childhood, Acta Orthopaedica 2009; 80 (6): 704-10. Long-term psychosocial functioning after Ilizarov limb lengthening during childhood: 37 patients followed for 2–14 years. Free access. <br /></span></p><p><span style="font-family: verdana;">16. <a href="https://www.blogger.com/#">Kim, SJ</a>., Balce, G.C., Agashe, M.V. et al. Is Bilateral Lower Limb Lengthening Appropriate for Achondroplasia?: Midterm Analysis of the Complications and Quality of Life. Clin Orthop Relat Res 2012; 470: 616–21. Free access.<br /><br /><br /><br /><br /></span></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com1tag:blogger.com,1999:blog-4791085249231790709.post-15783762780060335792021-11-10T23:02:00.004-05:002021-11-16T14:40:00.447-05:00Treating achondroplasia: from dream to reality<p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><b><i>The future is at our door </i></b><br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">We are now less than two weeks from Voxzogo's PDUFA* date, the day when the Food and Drug Administration (FDA) will release its response to vosoritide's application for commercialization. Vosoritide has been under clinical development for about ten years now, being investigated as a therapy for achondroplasia, the most common form of dwarfism. This long run has been taken with several humps and bumps throughout the way and, now that the drug is already approved in Europe, the expectations are all on how, and if, the decision by the FDA will truly open new doors for families interested in improving the health of their affected children. But let's see what these expectations are all about since the next steps may come with surprises. <br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">As the 17 readers of this blog certainly know, achondroplasia is caused by a mutation on the gene that encodes an enzyme called <i>fibroblast growth factor receptor 3 </i>(FGFR3). I know, I know, I might become a little bit repetitive, but I think that the circle I will be doing here might help us to understand what we may expect on that vosoritide's breakthrough date (PDUFA). </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><i><b>Causes and consequences </b></i><br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">FGFR3, along with many other enzymes, plays a fundamental role during the phase scientists call <i>development</i>. Development starts with the fertilized egg and goes up until the end of puberty, and it is comprised by biological processes tightly regulated by hundreds of enzymes like FGFR3. You could call these processes <i>standard operating procedures</i> (SOPs). These enzymes work in concert to make the SOPs to run smoothly, but when one of them is modified (mutated) either working more than planned or not working at all, then the development process is deranged. </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">FGFR3 is particularly important in bone development because it works by reducing the pace of bone growth, modulating the growth stimuli produced by several other enzymes. In a car, while those other enzymes would work as an accelerator, FGFR3 is a brake. If there was no FGFR3, bones would grow without control and cause several medical problems. In fact, mutations in FGFR3 that inactivate it do cause an overgrowth syndrome known as CATSHL syndrome (camptodactyly, tall stature, scoliosis and hearing loss) (1).</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">A brake is important in a car, so its speed can be controlled. However, the mutation in FGFR3 that causes achondroplasia makes it to work too much, so the car can barely move (the brake rules over the accelerator). The result is that, in achondroplasia, bones, and especially the long bones and vertebrae, grow just a fraction of what they were supposed to, in contrast with all other body tissues. Individuals with achondroplasia have short adult stature but this is not the only key characteristic since restricted skeletal growth has consequences beyond height. </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">The imbalance between shorter or narrow bones compared to all the other normal tissues will frequently lead to clinical complications that are listed in the published guidelines about achondroplasia. Due to their bone growth impairment, on average individuals with achondroplasia require more healthcare utilization, including surgical treatment to common orthopedic and neurological complications (e.g.: foramen magnum stenosis, spinal stenosis, joint problems, etc.) among others, while adults are also prone to obesity, higher incidence of cardiac disorders and have a shorter life span compared to the general population. (2)</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">As the knowledge about the natural history of achondroplasia improves it becomes clear that it is a genetic disorder affecting much more than the final height. </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><i><b>Developing the first therapy for achondroplasia</b></i><br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">The gene alteration that leads to achondroplasia was identified almost 30 years ago (3-5), but only more recently efforts have been directed to find ways to correct the bone growth defect caused by the overactive FGFR3 mutation. This became possible because the chemical networks regulated by FGFR3 have been identified (Figure 1) as well as of most of those pathways driven by the other agents involved in bone development and growth. This in turn allowed scientists to find out which of those pathways were impacted by mutations in FGFR3. (6) </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">Figure 1. FGFR3 relevant pathways in the chondrocyte.</span></span></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-family: verdana;"><span><span><span style="font-size: small;"><br /><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-TCJnxi7B-0_3w-7NBTcoK-4_HZPExvJRQ1iIXHofdXIWBdPwwrxEiOERmeMxeY9DqiT_Xla_En5e82NlrHbVw5sGsmHaS5cSijAD42DMrN5vvhAHq5Wi4FNNE5fBp20HlaREqR3qKjU/s602/FGFR3ModelNature.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="580" data-original-width="602" height="482" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi-TCJnxi7B-0_3w-7NBTcoK-4_HZPExvJRQ1iIXHofdXIWBdPwwrxEiOERmeMxeY9DqiT_Xla_En5e82NlrHbVw5sGsmHaS5cSijAD42DMrN5vvhAHq5Wi4FNNE5fBp20HlaREqR3qKjU/w500-h482/FGFR3ModelNature.jpg" width="500" /></a></span></span></span></span></div><span style="font-family: verdana;"><span><span><span style="font-size: small;"><br /></span></span></span></span><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">One of those other bone development agents is an enzyme called <i>natriuretic peptide receptor B</i> (NPR-B). Both FGFR3 and NPR-B are located in the cell membrane of the chondrocytes, the cells that govern bone growth. They can be seen as power switches in our home walls that are turned on and off when we move them up and down. In the body, FGFR3 is turned on by FGFs while NPR-B is activated by the <i>C-type natriuretic peptide</i> (CNP). Scientists have discovered that CNP is a positive bone growth agent that works precisely reducing the activity of FGFR3 in the chondrocyte. (Figure 2). They have also seen that the FGFR3 pathway may downregulate the CNP+NPR-B axis. (7)</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">Figure 2. Crosstalk of FGFR3 and CNP pathways in the chondrocyte.<br /></span></span></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="font-family: verdana;"><span><span><span style="font-size: small;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjGLRSit8mMCDFcUIebT2tFQg3AaDbgNVhQU07yrt618aFmt-g73oguFNl7vcFVu5b8IngkM7nDTZhg_MI1_2a-kVIN2kM7jw32eFkI_D8m5DPtLnBg_Yv3EgCfcNmtfSERWvF7_BJswtU/s557/william-horton+FGFR3_CNP+crosstalk.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="409" data-original-width="557" height="336" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjGLRSit8mMCDFcUIebT2tFQg3AaDbgNVhQU07yrt618aFmt-g73oguFNl7vcFVu5b8IngkM7nDTZhg_MI1_2a-kVIN2kM7jw32eFkI_D8m5DPtLnBg_Yv3EgCfcNmtfSERWvF7_BJswtU/w457-h336/william-horton+FGFR3_CNP+crosstalk.jpg" width="457" /></a></span></span></span></span></div><span style="font-family: verdana;"><span><span><span style="font-size: small;"><br /> <br /></span></span></span></span><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">Having learned that CNP modulates FGFR3 activity and that it was working less than normal in achondroplasia, it was natural to check out if providing supplemental CNP would help reducing the effects of the mutated FGFR3. In fact, this was readily seen: adding CNP to cell cultures, bone explants and animal models of achondroplasia restored, at least partially, bone growth. (8) A first potential therapy for achondroplasia was at hand. <br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">However, one problem that scientists faced when dealing with CNP is that this is a fragile molecule. Peptides like CNP are very active and must stay under control. When in the blood CNP will last less than three minutes circulating as it is an easy target for natural clearing systems we have. So, how to solve this problem? They learned that another natriuretic peptide called BNP is naturally more resistant to the clearing system due to having a slightly different structure. They adapted CNP to "look like" BNP and this change rendered the invention of vosoritide. (9) Therefore, vosoritide is a modified version of CNP, also called an analogue.</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">Vosoritide lasts about 20 minutes in the blood, enough time to reach the bone growth zones (the growth plates) and to exert its effects. So, what are these effects ? By reducing FGFR3 activity the NPR-B axis restores the chondrocyte capability to proliferate and enlarge (hypertrophy), which are the two key steps they need to take to make the bones grow. (8)</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">One hard challenge in the
beginning of the clinical development of vosoritide must have been how
to measure its efficacy. In humans, bone growth constitutes a long and
slow process so changes are not identified in a day-to-day basis, but
can only be seen when two distant time points are compared. This slow
development makes it difficult to set objectives when someone is trying
to correct a derangement in the bone growth process. Even harder would
be to confirm whether the improved bone growth under the experimental
drug would provide additional benefits in terms of reducing the frequent
medical complications that result from the short and narrow bones, such
as spinal stenosis. So, how can we measure those effects? After long
discussions, as we can see described in the many public calls (mostly those
financial conferences) throughout the years, the agreed endpoint between the developer and regulators that
would allow determining if vosoritide was beneficial (efficacy) in the
treatment of achondroplasia was <i>bone growth velocity</i>.</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">Vosoritide has been under tests in children with achondroplasia for years now and, according to the data already available, it helps to restore bone growth to an extent that is close to what happens in an average child. (10-12) The data that have been submitted to the European Medicines Agency (EMA) have been analyzed and, in last August, vosoritide was <a href="https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3121094">approved</a> for the treatment of achondroplasia in the European countries that work with that agency. The same data have also been submitted to the Food and Drug Administration (FDA) which will be delivering their feedback in a few days more, as I mentioned above.</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><i><b>The future is present</b></i> <br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">The approval of vosoritide in Europe is a landmark for the treatment of achondroplasia and very likely to many other skeletal dysplasias where bone growth is impaired. One important characteristic of the CNP+NPR-B axis is that it works independently of FGFR3. The use of CNP analogues like vosoritide (there are others in development) may help improve bone growth in those other genetic disorders, thus not only improving height, but also medical complications related to other restricted growth conditions, as we expect to see in achondroplasia. <br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">It may take a few years more to see whether children being treated with vosoritide will suffer fewer complications such as middle ear infections, sleep apnea, spinal stenosis, <i>genu varum</i>, etc. than what is frequently seen today, but the long term expectations about these potential benefits should not drive any conclusion that this drug, and all the other candidates to come, would not help to reduce those complications. </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">And why is that so? Simply because the treatment is systemic, meaning that the drug reaches all bones at the same time. There is no logic in thinking that only one type of bone would be affected by the treatment. Therefore, the treatment not only should increase the length of long bones but also should help widening other bones such as the vertebrae, which grow through growth plates, too.</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><i><b>Children's health</b></i></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">Here is the <a href="https://www.who.int/about/governance/constitution">World Health Organization definition of health</a>:</span></span></span></span></p><ul style="text-align: left;"><li><span style="font-family: verdana;"><span><span><span style="font-size: small;">Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.</span></span></span></span></li></ul><span style="font-family: verdana;"><span><span><span style="font-size: small;">The accumulating evidence about the natural history of achondroplasia shows that both children and adults with this skeletal dysplasia endure impacts not only on the physical aspect but both in the mental (emotional) and social well being fields, too.(13,14) It will be good to see how the upcoming pharmacological treatments for achondroplasia will affect these aspects of health. Based on published evidence, individuals submitted to limb lengthening have improved quality-of-life after the surgery (15, 16), implying that the improved height was beneficial on those other aspects of health highlighted in the WHO definition. Someone pondering about this improvement seen after lengthening surgery needs to recall that the surgery only increases height, not having any effect in other characteristics of achondroplasia and its common complications, in contrast with what is expected with pharmacological therapies. </span></span></span></span><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">We can foresee a time when
babies and toddlers with achondroplasia won't need MRIs to rule out foramen magnum
stenosis, or children attending repeated visits to a ENT specialist to insert ear
tubes, or undergo amigdalectomy to improve their sleep apnea, just to
cite a few of the stressful situations they frequently endure early in
life. They might also be able to do anything an average child does, without common challenges they face today due to their restricted growth.<br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">In conclusion, based on the current evidence, I believe that with improved bone growth, children with achondroplasia under treatment with vosoritide, and in the future with other potential therapies, will achieve benefits that go beyond the reduction of the risk of medical complications but also to improvement in mental and social aspects as well. These potential benefits must be kept in mind by stakeholders that will be in charge to decide whether to adopt therapies for achondroplasia or not. For me, the simple answer is yes.<br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><i><b>References</b></i><br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">* From Wikipedia: PDUFA date: In United States pharmaceutical regulatory practice, the PDUFA date is the colloquial name for the date by which the Food and Drug Administration must respond to a New Drug Application or a Biologics License Application.</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">1. <a href="https://www.sciencedirect.com/science/article/pii/S0002929707608362/pdfft?md5=74246b7164bc40c0a835de99c9c0e575&pid=1-s2.0-S0002929707608362-main.pdf">Toydemir RM</a>, Brassington AE, Bayrak-Toydemir P et al. Novel mutation in FGFR3 causes Camptodactyly, Tall Stature, and Hearing Loss (CATSHL) Syndrome. AGHG 2006; 79 (5): 935-41. <i>Free access.</i><br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">2. <a href="https://doi.org/10.1542/peds.2020-1010">Hoover-Fong J</a>, Scott CI, Jones MC et al. Health supervision for people with achondroplasia. Pediatrics 2020 Jun;145(6):e20201010.<i> Free access.</i><br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">3. <a href="https://idp.nature.com/authorize/casa?redirect_uri=https://www.nature.com/articles/371252a0.pdf%3Forigin%3Dppub&casa_token=CagN5vd-8yMAAAAA:fU7SLsofnSV1NKdNNkQ4_8anxGww5UGBC3vDhkP_USnr4w8gYvC79_gvt9FnW_oHnSDOz6snydh6Wm95Pg">Rousseau F,</a> Bonaventure J, Legeai-Mallet L et al., Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994; 371 (6494); 252–54. <i>Free access.</i></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">4. <a href="https://pubmed.ncbi.nlm.nih.gov/7913883/">Shiang R</a>, Thompson LM, Zhu YZ et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78 (2): 335–42.</span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">5. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1801129/pdf/ajhg00028-0015.pdf">Bellus GA</a>, Hefferon TW, Ortiz de Luna R et al. Achondroplasia is defined by recurrent G380R<br />mutations of FGFR3. Am J Hum Genet 1995; 56:368-73. <i>Free access.</i></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">6. <a href="https://doi.org/10.1016/j.bone.2020.115579">Legeai-Mallet L</a> and Savarirayan R. Novel therapeutic approaches for the treatment of achondroplasia. Bone 2020; 1<span class="cit">41:115579. </span><i>Free access.</i></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">7. <a href="https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/144484/1/yigak02905.pdf">Ozasa A</a>, Y. Komatsu A. Yasoda M et al. Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 2005; 36: 1056-64. <i>Free access.</i></span></span></span></span> </p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">8.<span class="period"> <a href="https://doi.org/10.1016/j.ajhg.2012.10.014">Lorget F</a>, Kaci N, Peng J et al. </span>Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia Am J Med Gen<span class="period"> </span><span class="cit">2012; 91(6):1108-14. <i>Free access.</i></span></span></span></span></span>
</p><span style="font-family: verdana;"><span><span><span style="font-size: small;"><span class="authors-list-item"><span class="comma">9. </span></span><span class="authors-list-item"><span class="comma"><span class="docsum-authors full-authors"><a href="https://doi.org/10.1124/jpet.114.218560">Wendt DJ</a>, Dvorak-Ewell M, Bullens S et al. </span></span></span>Neutral
endopeptidase-resistant C-type natriuretic peptide variant represents a
new therapeutic approach for treatment of fibroblast growth factor
receptor 3-related dwarfism.
<span class="docsum-journal-citation full-journal-citation">J Pharmacol Exp Ther 2015;353(1):132-49</span>.
</span></span></span></span><div class="docsum-citation full-citation">
<span style="font-family: verdana;"><span><span><span style="font-size: small;"><span class="docsum-authors full-authors"><br /></span></span></span></span></span></div><div class="docsum-citation full-citation">
<span style="font-family: verdana;"><span><span><span style="font-size: small;">10. <a href="https://pubmed.ncbi.nlm.nih.gov/31269546/"> </a> <a href="https://www.nejm.org/doi/pdf/10.1056/NEJMoa1813446?articleTools=true">Savarirayan R</a>, Irving M, Bacino CA et al. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med 2019; 381(1):25-35. <span class="cit"><i>Free access.</i></span></span></span></span></span></div><div class="docsum-citation full-citation"><span style="font-family: verdana;"><span><span><span style="font-size: small;"> </span></span></span></span></div><div class="docsum-citation full-citation"><span style="font-family: verdana;"><span><span><span style="font-size: small;">11.<span class="authors-list-item"> <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31541-5/fulltext">Savarirayan R</a><span class="comma">, T</span></span><span class="authors-list-item"><a class="full-name" data-ga-action="author_link" data-ga-category="search" data-ga-label="Louise Tofts">ofts L</a><span class="comma">, </span></span><span class="authors-list-item"><a class="full-name" data-ga-action="author_link" data-ga-category="search" data-ga-label="Melita Irving">Irving M.</a></span> Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet 2020; 396(10252):684-692. <span class="cit"><i>Free access.</i></span></span></span></span></span></div><span style="font-family: verdana;"></span><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">12. </span></span><span><span style="font-size: small;"><span class="authors-list-item"> <a href="https://doi.org/10.1038/s41436-021-01287-7">Savarirayan R</a><span class="comma">, T</span></span><span class="authors-list-item"><a class="full-name" data-ga-action="author_link" data-ga-category="search" data-ga-label="Louise Tofts">ofts L</a><span class="comma">, </span></span><span class="authors-list-item">Irving M.</span></span></span> Safe and persistent growth-promoting effects of vosoritide in children
with achondroplasia: 2-year results from an open-label, phase 3
extension study. Genet Med 2021 Aug 2;1-5. doi: 10.1038/s41436-021-01287-7. </span><span><span><span style="font-size: small;"><span class="cit"><i>Free access.</i></span></span></span></span></span></p><div class="article-citation"><div class="article-source"><span style="font-family: verdana;"></span></div></div><p><span style="font-family: verdana;"><span><span><span style="font-size: small;"> </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">13. <a href="https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1171-9">Witt S</a>, Kolb B, Bloemeke J et al. Quality of life of children with achondroplasia and their parents - a German cross-sectional study<span class="period">. Orphan J Rare Dis </span><span class="cit">2019;14(1):194. <i>Free access.</i></span> </span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">14. <a href="https://pubmed.ncbi.nlm.nih.gov/33369042/">Yonko EA</a>, Emanuel JS, Carter EM et al. Quality of life in adults with achondroplasia in the United States. Am J Med Gen 2021; 185(3):695-701.</span></span></span></span></p><p> </p><p><span style="font-family: verdana;"><span><span><span style="font-size: small;">15. <a href="https://doi.org/10.3109/17453670903473024">Moraal JM</a>,
Elzinga-Plomp A, Jongmans MA et al. Long-term psychosocial functioning
after Ilizarov limb lengthening during childhood, Acta Orthopaedica
2009; 80 (6): 704-10. Long-term psychosocial functioning after Ilizarov
limb lengthening during childhood: 37 patients followed for 2–14 years. <i>Free access.</i> <br /></span></span></span></span></p><p><span style="font-family: verdana;"><span><span><span><span style="font-size: small;">16. <a href="https://www.blogger.com/#">Kim, SJ</a>., Balce, G.C., Agashe, M.V. et al. Is Bilateral Lower Limb Lengthening Appropriate for Achondroplasia?: Midterm Analysis of the Complications and Quality of Life. Clin Orthop Relat Res 2012; 470: 616–21. <i>Free access.</i></span></span></span><br /></span></span></p><p><span style="font-family: trebuchet;"><br /></span></p><p><span style="font-family: trebuchet;"> </span></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com1tag:blogger.com,1999:blog-4791085249231790709.post-24232155205116874162021-08-27T10:59:00.002-04:002021-08-27T10:59:32.486-04:00Treating achondroplasia: vosoritide approved in Europe for the treatment of achondroplasia<p>This is a major breakthrough. The European Medicines Agency (EMA) has just released their decision to approve Voxzogo (vosoritide) for the treatment of achondroplasia in children two year-old and older until their growth plates close.</p><p><a href="https://www.ema.europa.eu/en/medicines/human/summaries-opinion/voxzogo">EMA approval decision.</a></p><p>This approval comes not far behind the recent decision by the French health authority to grant temporary approval for vosoritide in children 5+ years of age in July. You can read the French authorization and prescription protocol <a href="file:///C:/Users/Morrys/AppData/Local/Temp/20210716-atuc-voxzogo-put.pdf">here</a> (in French).<br /></p><p>You can read the Biomarin's press release <a href="https://investors.biomarin.com/2021-08-27-European-Commission-Approves-BioMarins-VOXZOGO-R-vosoritide-for-the-Treatment-of-Children-with-Achondroplasia-from-Age-2-Until-Growth-Plates-Close">here</a>. </p><p>Great news for so many children in the world!<br /></p><br />Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-5295422604410933562021-07-15T21:53:00.000-04:002021-07-15T21:53:17.889-04:00Treating achondroplasia: nine years online<p><span style="font-family: verdana;"><span> The blog "Treating achondroplasia" turned nine years old this year. When I started to write the articles for the blog the landscape was completely different: there was </span></span><span style="font-family: verdana;"><span>really </span></span><span style="font-family: verdana;"><span>nothing in the horizon towards therapeutic strategies for achondroplasia. Individuals with achondroplasia could only - and, as matter of fact, this is </span><span>still </span><span>true today - rely on surgical procedures to correct or improve skeletal problems which come with the typical bone growth impairment caused by the overactive<i> fibroblast growth factor receptor 3</i> (FGFR3) mutation. Infants with <i>foramen magnum </i>stenosis, children with bowed legs, teens and adults with spinal stenosis </span></span><span style="font-family: verdana;"><span>sometimes </span></span><span style="font-family: verdana;"><span>must undergo several surgical interventions to control these and other common neurological and orthopedic complications seen in achondroplasia.<br /></span></span></p><p><span style="font-family: verdana;"><span>However, things are changing. There are now several potential pharmacological therapies in several stages of development as you can see in the last <a href="https://tratando-acondroplasia.blogspot.com/2021/01/treating-achondroplasia-2020-in-review.html">article </a>published in January in the blog. One of them, vosoritide, is in the last sprint towards approval by two of the most important world regulatory agencies, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Others still have to prove their safety and efficacy in clinical trials and most of them should reach the stage where vosoritide is now. If vosoritide data provided by the developer to EMA and FDA is sound and reliable it is expected that it will be approved and made available next year. This will become a turning point. </span></span></p><p><span style="font-family: verdana;"><span>Achondroplasia is a genetic disorder of bone development, meaning that the effects of the mutation in FGFR3 are restricted to the life interval when bones grow. </span></span><span style="font-family: verdana;"><span><span style="font-family: verdana;"><span>FGFR3
is a natural inhibitor of the bone growth process and, because of the
mutation, in achondroplasia it is working too much leading to growth
arrest.</span></span>The end of puberty also represents the end of the bone development process. Unfortunately, because of this, adult individuals would have no benefits in receiving a therapy against FGFR3, at least with the intent of achieving bone growth.</span></span></p><p><span style="font-family: verdana;"><span>Therapies for achondroplasia will benefit children and teenagers and it is expected that the earlier they start a therapy the better would be the outcomes, although this expectation still needs to be confirmed with data coming from the studies in younger children currently ongoing. </span></span></p><p><span style="font-family: verdana;"><span>Why is important to start the therapy early? Because it is during the first two years of life (and specially during the first year) that children experiment their highest growth velocity rate. </span><span>Of
course, achondroplasia is already identifiable before birth but it is
unlikely that a pharmacological intervention so early in life will be available soon. I</span><span>t is during the first two years of life that most of the clinical features of achondroplasia will be established so, if a therapy can be initiated early, it might more efficiently reduce or mitigate those features, which in turn might prevent the common complications I mentioned above.</span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: verdana;">The Treating Achondroplasia blog is active and I will keep publishing updates as relevant information is released. I really hope that the blog is helping the interested reader to better understand achondroplasia, FGFR3 and what to expect with the new therapies. See you soon. ;)</span><br /></span></p><p><span style="font-family: trebuchet;"> </span><br /></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-9879901114182594222021-01-01T16:26:00.003-05:002022-01-11T10:57:12.182-05:00Tratando a acondroplasia: uma revisão de 2020<p><i><b><span style="font-family: Open Sans;">Um ano difícil</span></b></i></p><p><span style="font-family: Open Sans;">Que ano difícil e desafiador para todos nós foi 2020. A pandemia do novo coronavírus tem causado tantos transtornos em nosso mundo que ninguém é capaz de dizer quando nossas vidas voltarão ao normal novamente. </span></p><p><span style="font-family: Open Sans;">Em um artigo anterior, mencionei que não queria ficar sempre repetindo as mesmas informações aqui e essa era a explicação para não postar com mais frequência no blog. Também mencionei que mantenho um grupo no Facebook chamado <a href="https://www.facebook.com/groups/achondroplasia" target="_blank">Achondroplasia</a>, onde os seguidores podem ficar por dentro das informações mais recentes sobre terapias para a acondroplasia à medida que são divulgadas ao público. Nesse sentido, o blog Tratando a Acondroplasia continua ativo, disponibilizando informações mais detalhadas sobre tratamentos para a acondroplasia a todos os interessados.</span></p><p><span style="font-family: Open Sans;"> De todo modo, houve tantas notícias novas no campo da acondroplasia em 2020 que achei que seria bom analisá-las em uma breve revisão aqui. Vamos começar verificando cada um dos principais tratamentos potenciais e apresentando os novos anunciados durante o ano. Na Tabela 1, você pode ver o status de desenvolvimento atual disponível publicamente. Todos eles, exceto o<i> inibidor de tirosina quinase</i> (TKI) ASP-5878, já foram revisados no blog. Para obter informações mais detalhadas sobre esses medicamentos, visite a página de índice para encontrar esses artigos.</span></p><p><span style="font-family: Open Sans;">Tabela 1. Lista de potenciais terapias para acondroplasia. </span></p><p><span style="font-family: Open Sans;"></span></p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhwQ1l0qE_9ZVrsungj2zj7vq_AMuDWLoFj-ajjgNIxgamuD8hEWi_iFSV0yOT68j-2NwJ_8sI88f3e-iy3KaofnFOhrxED4ede-8znu3TTuv9xwsf-Ck7Q5ZaLm9i8VDrrGokIvxKB7_Q/s1238/Tabela+1_31Dec20.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="741" data-original-width="1238" height="382" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhwQ1l0qE_9ZVrsungj2zj7vq_AMuDWLoFj-ajjgNIxgamuD8hEWi_iFSV0yOT68j-2NwJ_8sI88f3e-iy3KaofnFOhrxED4ede-8znu3TTuv9xwsf-Ck7Q5ZaLm9i8VDrrGokIvxKB7_Q/w640-h382/Tabela+1_31Dec20.jpg" width="640" /></a></td></tr><tr align="left"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: Open Sans;">CNP: peptídeo natriurético tipo C. SC: subcutâneo. MA: autorização de
comercialização. TKI: inibidor de tirosina quinase. NA: não disponível. <br /></span></span></td></tr></tbody></table><span style="font-family: Open Sans;"> </span><span style="font-family: Open Sans;"><br /></span><p></p><p><i><b><span style="font-family: Open Sans;">Vosoritide</span></b></i></p><p></p><p><span style="font-family: Open Sans;">A principal notícia sobre o vosoritide é que a Biomarin submeteu pedidos de autorização de comercialização às agências reguladoras europeia e americana (EMA e FDA) em agosto, com uma aprovação potencial estimada nos EUA em agosto de 2021. Em setembro, o desenvolvedor publicou os resultados completos do <a href="https://pubmed.ncbi.nlm.nih.gov/32891212/" target="_blank">estudo de fase 3</a> (1), que demonstraram uma melhora significativa na velocidade de crescimento com vosoritide em comparação com o placebo depois de um ano de tratamento. Mais recentemente, eles <a href="https://investors.biomarin.com/2020-12-21-BioMarin-Announces-Benefit-Maintained-for-Over-Two-Years-in-Children-with-Achondroplasia-Treated-with-Vosoritide-in-Phase-3-Extension-Study" target="_blank">anunciaram </a>que a melhora na velocidade de crescimento demonstrou ser sustentada após dois anos de terapia com vosoritide, semelhante ao que foi visto no estudo de extensão de longo prazo com participantes do estudo de fase 2. Além disso, o <a href="https://www.clinicaltrials.gov/ct2/show/NCT03583697" target="_blank">estudo de fase 2</a> com bebês e crianças pequenas (<5 anos) está em andamento. </span></p><p><span style="font-family: Open Sans;">Também recentemente, eles iniciaram um <a href="https://www.clinicaltrials.gov/ct2/show/NCT04219007?term=vosoritide&cond=Short+Stature&draw=2&rank=1" target="_blank">estudo </a>com o vosoritide em outras causas de baixa estatura. </span></p><p><span style="font-family: Open Sans;"> </span></p><p><span style="font-family: Open Sans;"><i><b>TransCon-CNP</b></i> </span></p><p><span style="font-family: Open Sans;">A principal diferença entre o TransCon-CNP e o vosoritide é que o TransCon-CNP é administrado por meio de um sistema de liberação lenta, permitindo uma dose semanal com exposição sustentada ao seu análogo, em contraste com a dosagem diária do vosoritide. Em estudos pré-clínicos, eles mostraram que seu análogo do CNP era superior ao vosoritide (2). A Ascendis Pharma iniciou o estudo de fase 2 <a href="https://www.clinicaltrials.gov/ct2/show/NCT04085523?term=ascendis&cond=achondroplasia&draw=2&rank=1" target="_blank">ACcomplisH</a> com TransCon-CNP e, de acordo com o site ClinicalTrials.gov, ainda estão aceitando candidatos.</span></p><p><i><b><span style="font-family: Open Sans;"> </span></b></i></p><p><i><b><span style="font-family: Open Sans;">Recifercept</span></b></i></p><p><span style="font-family: Open Sans;"> A molécula TA-46 original foi inicialmente desenvolvida pela Therachon como uma injeção subcutânea semanal (3). Em setembro, durante a Conferência de Pesquisa de Acondroplasia organizada pelo <a href="https://thechandlerproject.org/" target="_blank">Chandler Crews Project</a>, descobrimos que o laboratório agora está trabalhando com uma programação de dosagem diária dessa nova medicação. </span><span style="font-family: Open Sans;">No final de dezembro, a</span><span style="font-family: Open Sans;"> Pfizer publicou os testes pré-clínicos realizados com o recifercept, mostrando que essa molécula é, na verdade, o resultado de modificações feitas na molécula original TA-46 desenvolvida pela Therachon (4). O recifercept é uma forma livre modificada do <i>receptor de fator de crescimento de fibroblastos 3</i> (FGFR3) que funciona como uma "armadilha de ligante", capturando ativadores de FGFRs antes que eles possam se ligar a esses receptores e ativá-los. Sem os ativadores (ligantes), o FGFR3 não seria tão ativo quanto o esperado e isso ajudaria a restaurar o crescimento ósseo. Duas semanas atrás, a Pfizer anunciou o início de seu <a href="https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-12/Recifercept_PressStatement_vf_12142020.pdf?bmcijay_wZp3XqewDa_DXnr187LJeGo8" target="_blank">estudo de fase 2</a>.</span></p><p><span style="font-family: Open Sans;"> </span></p><p><b><i><span style="font-family: Open Sans;">Infigratinib</span></i></b></p><p><span style="font-family: Open Sans;">O infigratinib é um TKI oral desenvolvido inicialmente para tratar vários tipos de câncer em que os FGFRs, inclusive o FGFR3, desempenham um papel importante para a progressão da doença. Ele age bloqueando as cascatas de sinalização dos FGFRs dentro da célula. Dado que um FGFR3 anormal e superativo é a causa da acondroplasia, os pesquisadores procuraram descobrir se o infigratinib poderia ser usado para tratar esta displasia esquelética. Estudos pré-clínicos demonstraram que ele realmente resgata o crescimento ósseo em um modelo de acondroplasia de camundongo em doses muito mais baixas do que aquelas usadas nos primeiros estudos em câncer (5). Durante o congresso ENDO 2020 eles apresentaram um <a href="https://www.qedtx.com/wp-content/uploads/Demuynck-ENDO-2020-achondroplasia-poster-24-Apr-2020.pdf" target="_blank">pôster </a> com testes pré-clínicos realizados com infigratinib mostrando melhora significativa do crescimento ósseo e nenhum efeito no metabolismo do fósforo com doses baixas, semelhantes às pretendidas para ensaios clínicos (6). Essa informação sobre o metabolismo do fósforo é importante do ponto de vista da segurança da medicação. Nesses estudos, eles também verificaram que o infigratinib foi superior ao vosoritide no resgate do crescimento ósseo. A QED iniciou recentemente seu <a href="https://www.clinicaltrials.gov/ct2/show/NCT04265651?term=QED&cond=achondroplasia&draw=2&rank=2" target="_blank">estudo de fase 2</a> com infigratinib.</span></p><p><span style="font-family: Open Sans;"> </span></p><p><i><b><span style="font-family: Open Sans;">Meclizina</span></b></i></p><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;">O reaproveitamento de medicamentos é uma estratégia em que os investigadores tentam encontrar novas indicações terapêuticas para medicamentos antigos. O conceito é que a pesquisa para a nova indicação seja muito menos cara e o custo final do medicamento, se aprovado, seja certamente mais acessível do que o de compostos recém-criados. A meclizina é um medicamento antigo que há décadas</span><span style="font-family: Open Sans;"> tem sido</span><span style="font-family: Open Sans;"> usado para tratar o enjôo de movimento. Em um esforço para encontrar tratamentos potenciais para a acondroplasia, o grupo japonês da Universidade de Nagoya liderado pelo Dr. Kitoh descobriu que a meclizina foi capaz de inibir a função do FGFR3 e resgatar parcialmente o crescimento ósseo em seu modelo animal (7). Posteriormente, eles realizaram um <a href="https://dx.plos.org/10.1371/journal.pone.0229639" target="_blank">estudo de fase 1</a> em crianças com acondroplasia (8). O estudo mostrou que a meclizina pode ser adequada em uma única dose diária (mas isso precisa ser explorado em estudos subsequentes). Eles planejavam iniciar um estudo de fase 2 em 2020, mas não encontrei atualizações sobre o status desse programa.</span></p><p><span style="font-family: Open Sans;"> </span></p><p><i><b><span style="font-family: Open Sans;">RBM-007</span></b></i></p><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;">A Ribomic vem desenvolvendo o RBM-007, um aptâmero anti-FGF2 desenvolvido para tratar condições em que o FGF2 tem um papel relevante no mecanismo da doença (9). Uma vez que o FGF2 é considerado um ativador </span><span style="font-family: Open Sans;"> (ligante) </span><span style="font-family: Open Sans;">chave do FGFR3 e que na acondroplasia o FGFR3 é hiperativo, então se esse fosse menos ativado pelo FGF2 talvez o crescimento ósseo pudesse ser restaurado. Em seu site, a Ribomic menciona que em <a href="https://www.ribomic.com/eng/pipeline/rbm007.php/#clinicals_01" target="_blank">estudos pré-clínicos</a> o RBM-007 de fato resgatou o crescimento ósseo (mas não consegui encontrar nenhum artigo publicado mostrando seus resultados em um modelo de acondroplasia). Eles já começaram um <a href="https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?directLink=0p52SZqEULFxxBQ0QuD.Vg--" target="_blank">estudo clínico de fase 1</a> para avaliar este aptâmero para a acondroplasia.</span></p><p><span style="font-family: Open Sans;"> </span></p><p><i><b><span style="font-family: Open Sans;">ASP-5878</span></b></i></p><p><span style="font-family: Open Sans;">A Astellas Pharma publicou recentemente um estudo onde explorou o uso de ASP-5878, um TKI semelhante ao infigratinib, em modelos pré-clínicos para tratar a acondroplasia (10). Eles descobriram que a droga era capaz de melhorar o crescimento ósseo, porém era menos eficaz em comparação com um controle positivo, um análogo do CNP com a mesma estrutura do vosoritide.</span></p><p><span style="font-family: Open Sans;"> </span></p><p><i><b><span style="font-family: Open Sans;">ASB-20123</span></b></i></p><p><span style="font-family: Open Sans;">Asubio, uma empresa de biotecnologia japonesa que foi recentemente incorporada pela Daichii-Sankio (DK), estava desenvolvendo outro análogo do CNP com base na fusão do fragmento ativo do CNP e um fragmento da base estrutural do hormônio <i>grelina </i>para ajudar a melhorar a conhecida meia-vida curta do CNP. Eles publicaram alguns estudos mostrando que sua molécula foi capaz de melhorar o crescimento ósseo em modelos pré-clínicos (11), mas não consegui encontrar nenhuma nova notícia sobre esse composto no site da DK ou na literatura.</span></p><p><span style="font-family: Open Sans;"> </span></p><p><span style="font-family: Open Sans;"><i><b>Referências</b></i></span></p><p><span style="font-family: Open Sans;"><b><span style="font-family: Open Sans;">1.<a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31541-5/fulltext" target="_blank"> Savarirayan R et al</a>.</span><span style="font-weight: normal;"><span style="font-size: small;"><span style="font-family: Open Sans;"> </span></span></span></b><span style="font-size: small;"><span><span style="font-family: Open Sans;">Once-daily, subcutaneous vosoritide therapy in
children with achondroplasia: a randomised, double-blind, phase 3,
placebo-controlled, multicentre trial.</span></span><span style="font-family: Open Sans;"> Lancet 2020; 396 (10257):1070.</span></span></span></p><p><span style="font-family: Open Sans;">2.</span> <span style="font-family: Open Sans;"><a href="https://jpet.aspetjournals.org/content/370/3/459.long" target="_blank">Breinholt VM et al</a>.
TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a
Potentially Safe and Efficacious New Therapeutic Modality for the
Treatment of Comorbidities Associated with Fibroblast Growth Factor
Receptor 3-Related Skeletal Dysplasias. J Pharmacol Exp Ther 2019;
370(3): 459-71. <i>Open access.</i></span><span class="authors-list-item"></span></p><p><span style="font-family: Open Sans;">3.<a href="https://stm.sciencemag.org/content/5/203/203ra124" target="_blank"> Garcia S et al</a>. Postnatal soluble FGFR3 therapy rescues achondroplasia
symptoms and restores bone growth in mice. Sci Transl Med 2013; 5 (203):203ra124. <i>Open access after registration.</i> <br /></span></p><p><span style="font-family: Open Sans;">4. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244368" target="_blank">Gonçalves D et al</a>. <i>In vitro</i> and <i>in vivo</i>
characterization of Recifercept, a soluble fibroblast growth factor
receptor 3, as treatment for achondroplasia. PLoS ONE 2020; 15(12):
e0244368. <i>Open access</i>.</span><br /></p><span style="font-family: Open Sans;">5. <a href="https://www.jci.org/articles/view/83926" target="_blank">Komla-Ebri D et al</a>.
Tyrosine kinase inhibitor NVP-BGJ398 functionally improves
FGFR3-related dwarfism in mouse model. J Clin Invest 2016;
126(5):1871-84. <i>Open access.</i><br /></span><div class="article-citation">
<span class="citation-doi"></span><span class="secondary-date"></span>
</div>
<span class="authors-list-item"><span class="comma"></span></span><p><span style="font-family: Open Sans;">6. <a href="https://www.qedtx.com/wp-content/uploads/Demuynck-ENDO-2020-achondroplasia-poster-24-Apr-2020.pdf" target="_blank">Demuynck B et al</a>.
Support for a new therapeutic approach of using a low-dose FGFR
tyrosine kinase inhibitor (infigratinib) for achondroplasia. Approved by
but not presented at ENDO 2020 due to COVID-19 pandemics. Acessed on
01-Jan-2021. <i>Open access.</i><br /></span></p><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;">7. </span><span style="font-family: Open Sans;"><span class="docsum-authors full-authors"><a href="https://academic.oup.com/endo/article/156/2/548/2422492" target="_blank">Matsushita M et al</a>.</span></span><span style="font-family: Open Sans;"><span class="docsum-authors full-authors"></span></span><span style="font-family: Open Sans;"> </span><span style="font-family: Open Sans;">Meclozine
promotes longitudinal skeletal growth in transgenic mice with
achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.
<span class="docsum-journal-citation full-journal-citation">Endocrinology 2015; 156(2):548-54. </span></span><span style="font-family: Open Sans;"><span class="docsum-journal-citation full-journal-citation"><span style="font-family: Open Sans;"><i>Open access.</i></span></span></span></p><p><span style="font-family: Open Sans;">8. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229639" target="_blank"><span class="authors-list-item">Kitoh H</span></a><span class="period"><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229639" target="_blank"> et al</a>. </span>Pharmacokinetics and safety after once and twice a day doses of
meclizine hydrochloride administered to children with achondroplasia. PLoS ONE 2020<span class="cit">;15(4):e0229639. </span></span><span style="font-family: Open Sans;"><span class="docsum-journal-citation full-journal-citation"><span style="font-family: Open Sans;"><i>Open access.</i></span></span></span>
</p><span style="font-family: Open Sans;">9. <a href="https://www.sciencedirect.com/science/article/pii/S1525001616454535" target="_blank">Ling Jin et al.</a>
Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone
Disease and Bone Cancer Pain. Mol Ther 2016; 24 (11): 1974-1986. <i>Open access.</i><br /></span><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;">10. <a href="https://www.nature.com/articles/s41598-020-77345-y#Sec19" target="_blank">Ozaki T et al</a>. Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia.<span style="font-family: inherit;"> Sci Rep 2020; 10: 20915. <i>Open access</i>.</span></span></p><p><span style="font-family: Open Sans;"><span style="font-family: inherit;">11.</span></span><span style="font-family: Open Sans;"></span><span style="font-family: Open Sans;"><span style="font-family: inherit;"> </span><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680" target="_blank">Morozumi N et al</a>.
ASB20123: A novel C-type natriuretic peptide derivative for treatment
of growth failure and dwarfism. PLoSONE 2019;14(2):e0212680. </span><span style="font-family: Open Sans;"><span style="font-family: Open Sans;"><span style="font-family: inherit;"><i>Open access</i>.</span></span></span></p><p><span style="font-family: Open Sans;"><i><b> </b></i><br /><br /><br /><br /><br /> <br /><br /> </span></p><p><span style="font-family: Open Sans;"> </span></p><p><span style="font-family: Open Sans;"> </span></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-23875810388352569892021-01-01T13:30:00.008-05:002021-11-17T12:45:53.762-05:00Treating achondroplasia: 2020 in review<p><span style="font-family: Open Sans;"><i><b>A tough year </b></i><br /></span></p><p><span style="font-family: Open Sans;">This 2020 was tough, challenging year for all of us. The new coronavirus pandemic has been causing so much disruption in our world and nobody can say when our lives will be back (or close to) normal again.</span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">In a previous article, I mentioned that I didn't want to just keep repeating the same information over and over again here and that was the explanation for not posting more frequently in the blog. I have also mentioned that I keep a Facebook group called <a href="https://www.facebook.com/groups/achondroplasia" target="_blank">Achondroplasia</a>, where followers can stay on top of the newest information about therapies for achondroplasia as they are released to the public. In this sense, the blog <b>Treating Achondroplasia</b> keeps being active, providing more in depth information to all interested people.<br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">Notwithstanding, there have been so many new research developments in the achondroplasia field in 2020 that I thought it would be good to go through them in a short review here. </span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">Let's start checking out each of the main potential treatments and introducing the new ones announced during the year. In Table 1 you can see their current development status as publicly available. All of them but </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">the <i>tyrosine kinase inhibitor</i> (TKI) ASP-5878</span></span> have </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">already </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">been reviewed in the blog. To get more detailed information about these drugs just visit the index page to find those articles.</span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">Table 1. List of potential therapies for achondroplasia.</span></span></p><i><b><span style="font-family: Open Sans;"><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><span style="font-family: trebuchet;"><span style="font-size: x-small;"><span style="font-family: Open Sans;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgHOYFOxGKRxo76X4e8-maMs-h9aC0_qq9dBCpwM2Uhc9a9RaUWuTVcsdXfuQ1G2KmaMnTP86zvui7U0SiGsVWu_F_Y6FVE3m5xUlHAYQF1jB_r-V6KBct2HZXg0jk-eBHgCr1qqET_T7w/s1238/Table+1_31Dec20.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="665" data-original-width="1238" height="344" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgHOYFOxGKRxo76X4e8-maMs-h9aC0_qq9dBCpwM2Uhc9a9RaUWuTVcsdXfuQ1G2KmaMnTP86zvui7U0SiGsVWu_F_Y6FVE3m5xUlHAYQF1jB_r-V6KBct2HZXg0jk-eBHgCr1qqET_T7w/w640-h344/Table+1_31Dec20.jpg" width="640" /></a></td></tr><tr align="left"><td class="tr-caption"><div style="margin-left: 40px;"><span style="font-size: x-small;">CNP: C-type natriuretic peptide. RoA: route of administration. </span><span style="font-size: x-small;">SC: subcutaneous. </span><span style="font-size: x-small;">MA: market authorization. TKI: tyrosine kinase inhibitor. NA: not available.</span></div></td></tr></tbody></table></span></span></span></span></span></span></b></i><i><b><span style="font-family: Open Sans;"><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><span style="font-family: trebuchet;"><span style="font-size: x-small;"><span style="font-family: Open Sans;"></span></span></span></span></span></span></b></i><p><i><b><span style="font-family: Open Sans;">Vosoritide</span></b></i></p><p><span style="font-family: Open Sans;"> The main news about vosoritide is that Biomarin has submitted market authorization applications both to the European and American regulatory agencies (EMA and FDA) back in August, with a potential approval estimated to be released in US by August 2021.</span></p><p><span style="font-family: Open Sans;">Back in September, the developer has published the full results from the <a href="https://pubmed.ncbi.nlm.nih.gov/32891212/" target="_blank">phase 3 study</a> (1), which demonstrated a significant improvement in growth velocity with vosoritide compared to placebo after one year. More recently they <a href="https://investors.biomarin.com/2020-12-21-BioMarin-Announces-Benefit-Maintained-for-Over-Two-Years-in-Children-with-Achondroplasia-Treated-with-Vosoritide-in-Phase-3-Extension-Study" target="_blank">announced</a> that the improvement in growth velocity has been shown to be sustained after two years of therapy with vosoritide, similar to what has been seen in the long term extension study with the participant of the phase 2 study. Furthermore, the <a href="https://www.clinicaltrials.gov/ct2/show/NCT03583697">phase 2 study</a> with </span><span style="font-family: Open Sans;">infants </span><span style="font-family: Open Sans;">and toddlers (<5 years old) is currently ongoing.<br /></span></p><p><span style="font-family: Open Sans;">Also recently, they have started a <a href="https://www.clinicaltrials.gov/ct2/show/NCT04219007?term=vosoritide&cond=Short+Stature&draw=2&rank=1" target="_blank">study</a> with vosoritide in other causes of short stature.<br /></span></p><p><i><b><span style="font-family: Open Sans;"><br /></span></b></i></p><p><i><b><span style="font-family: Open Sans;">TransCon-CNP</span></b></i></p><p><span style="font-family: Open Sans;">The main difference between TransCon-CNP and vosoritide is that TransCon-CNP is delivered through a slow release system allowing a weekly dose with sustained exposure to their analogue in contrast with vosoritide's daily dosing. In pre-clinical studies they showed that their CNP analogue was superior to vosoritide (2). </span><br /></p><p><span style="font-family: Open Sans;">Ascendis Pharma has started the phase 2 study </span><span style="font-family: Open Sans;"><a href="https://www.clinicaltrials.gov/ct2/show/NCT04085523?term=ascendis&cond=achondroplasia&draw=2&rank=1" target="_blank">ACcomplisH </a>with TransCon-CNP and, according with the site ClinicalTrials.gov they are still accepting candidates.</span></p><p><br /></p><p><i><b><span style="font-family: Open Sans;">Recifercept </span></b></i></p><p><span style="font-family: Open Sans;">The original TA-46 molecule has been initially developed by Therachon as a weekly subcutaneous injection (3). Back in September, during the Achondroplasia Research Conference organized by the <a href="https://thechandlerproject.org/" target="_blank">Chandler Crews Project</a>, we learned that the developer is now working with a daily dosing schedule. In the end of December Pfizer has published the pre-clinical tests performed with recifercept, showing that this molecule is, in fact, the result of modifications made in the original molecule TA-46 developed by Therachon (4). Recifercept is a modified, free form of the <i>fibroblast growth factor receptor 3</i> (FGFR3) that works as a "ligand trap", capturing FGFR activators before they can bind and activate these receptors, including FGFR3. Without the activators (ligands) FGFR3 would not be as active as expected and this would help restoring bone growth. Two weeks ago, Pfizer announced the start of their <a href="https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-12/Recifercept_PressStatement_vf_12142020.pdf?bmcijay_wZp3XqewDa_DXnr187LJeGo8">phase 2 study</a>.</span><i><b><span style="font-family: Open Sans;"> </span></b></i><br /></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p><i><b></b></i></p><p><i><b></b></i></p><p><i><b><span style="font-family: Open Sans;"></span></b></i></p><p><i><b><span style="font-family: Open Sans;"><br /></span></b></i></p><p><i><b><span style="font-family: Open Sans;">Infigratinib</span></b></i></p><p><span style="font-family: Open Sans;">Infigratinib is an oral TKI initially developed to treat several types of cancer where FGFRs play an important role for the progression of the disease. It works by blocking the FGFRs' signaling cascades inside the cell. Given that an abnormal, overactive FGFR3 is the cause of achondroplasia, investigators sought to find whether infigratinib could be used to treat this skeletal dysplasia. Preclinical studies demonstrated that it indeed rescues bone growth in a mouse model of achondroplasia, in doses much lower than those used in the first studies in cancer (5). </span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">They recently presented a <a href="https://www.qedtx.com/wp-content/uploads/Demuynck-ENDO-2020-achondroplasia-poster-24-Apr-2020.pdf" target="_blank">poster </a>in the ENDO 2020 meeting with pre-clinical tests performed with infigratinib showing significant improvement of bone growth and no effect on phosphorus metabolism with low doses similar to those intended for clinical trials (6). This is important from the safety standpoint. In those studies they also found that infigratinib was superior to vosoritide. </span></span><span style="font-family: Open Sans;">QED has recently started their <a href="https://www.clinicaltrials.gov/ct2/show/NCT04265651?term=QED&cond=achondroplasia&draw=2&rank=2">phase 2 study</a> with infigratinib.</span></p><p><span style="font-family: trebuchet;"></span></p><p><span style="font-family: trebuchet;"></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><i><b> </b></i></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><i><b>Meclizine</b></i> <br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">Drug repurposing is a strategy where investigators try to find new therapeutic indications for old drugs. The concept is that its development for the new purpose should be much less expensive and the final drug cost, if approved, would be surely more affordable than the cost of newly created compounds. Meclizine is an old drug that has been used to treat motion sickness for decades. In an effort to find potential treatments for achondroplasia the Japanese group from University of Nagoya leaded by Dr. Kitoh has found that meclizine was able to inhibit the FGFR3 function and to partially rescue bone growth in their animal model (7). They have subsequently conducted a <a href="https://dx.plos.org/10.1371/journal.pone.0229639">phase 1 study</a> in children with achondroplasia (8). The study showed that meclizine could be suitable for a single daily dose (but this needs to be further explored in subsequent studies). They were planning to start a phase 2 study during 2020, but I couldn't find any updates on the status of this program lately. <br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"> </span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><i><b>RBM-007</b></i> <br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"> Ribomic has been developing RBM-007, an anti-FGF2 aptamer developed to treat conditions where FGF2 has a relevant role in the mechanism of disease (9). Since FGF2 is considered a key activator (ligand) of FGFR3 and that in achondroplasia FGFR3 is overactive, then if it was less activated by FGF2 perhaps bone growth could be restored. In their website, Ribomic mentions that in <a href="https://www.ribomic.com/eng/pipeline/rbm007.php/#clinicals_01" target="_blank">preclinical studies</a> RBM-007 indeed rescued bone growth (but I could not find any published article showing their results in a model of achondroplasia). They have already started a <a href="https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?directLink=0p52SZqEULFxxBQ0QuD.Vg--">phase 1 clinical trial</a> to evaluate this aptamer for achondroplasia.<br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"> </span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><i><b>ASP-5878</b></i><br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">Astellas Pharma has recently published a study where they explored the use of ASP-5878, a TKI similar to infigratinib, </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">in pre-clinical models </span></span>to treat achondroplasia (10). They found that the drug was able to improve bone growth, however it was less effective compared to a </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">positive control, a </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">CNP analogue </span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">bearing the same structure of vosoritide</span></span><span style="font-family: trebuchet;"><span style="font-family: Open Sans;">. <br /></span></span></p><p><span style="font-family: trebuchet;"><span style="font-family: Open Sans;"> </span></span></p><p><span style="font-family: trebuchet;"><i><b><span style="font-family: Open Sans;">ASB-20123</span></b></i><br /></span></p><p><span style="font-family: Open Sans;"><i><b></b></i></span></p><p><span style="font-family: Open Sans;">Asubio, a Japanese biotech that was recently incorporated by Daichii-Sankio (DK), was developing another CNP analogue based in the fusion of the active fragment of CNP and a backbone fragment of the hormone ghrelin to help improving the known short half-life of CNP. They have published some studies showing that their molecule was able to improve bone growth in pre-clinical models (11) but I couldn't find any news about this compound in the DK website or in the literature.<br /><b></b><i><b> </b></i></span></p><p><span style="font-family: Open Sans;"><i><b> </b></i></span></p><p><span style="font-family: Open Sans;"><i><b>References</b></i><br /><br />1.<a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31541-5/fulltext" target="_blank"> Savarirayan R et al</a>.</span><span style="font-weight: normal;"><span style="font-size: small;"><span style="font-family: Open Sans;"> Once-daily, subcutaneous vosoritide therapy in
children with achondroplasia: a randomised, double-blind, phase 3,
placebo-controlled, multicentre trial.</span></span></span><span style="font-family: Open Sans;"> Lancet 2020; 396 (10257):1070.</span></p><p><span style="font-family: Open Sans;">2.</span> <span style="font-family: Open Sans;"><a href="https://jpet.aspetjournals.org/content/370/3/459.long" target="_blank">Breinholt VM et al</a>. TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias. J Pharmacol Exp Ther 2019; 370(3): 459-71. <i>Open access.</i></span><span class="authors-list-item"></span></p><p><span style="font-family: Open Sans;">3.<a href="https://stm.sciencemag.org/content/5/203/203ra124" target="_blank"> Garcia S et al</a>. Postnatal soluble FGFR3 therapy rescues achondroplasia
symptoms and restores bone growth in mice. Sci Transl Med 2013; 5 (203):203ra124. <i>Open access after registration.</i> <br /></span></p><p><span style="font-family: Open Sans;">4. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244368" target="_blank">Gonçalves D et al</a>. <i>In vitro</i> and <i>in vivo</i> characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia. PLoS ONE 2020; 15(12):
e0244368. <i>Open access</i>.</span><br /></p><span style="font-family: Open Sans;">5. <a href="https://www.jci.org/articles/view/83926" target="_blank">Komla-Ebri D et al</a>. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016; 126(5):1871-84. <i>Open access.</i><br /></span><div class="article-citation">
<span class="citation-doi"></span><span class="secondary-date"></span>
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<span class="authors-list-item"><span class="comma"></span></span><p><span style="font-family: Open Sans;">6. <a href="https://www.qedtx.com/wp-content/uploads/Demuynck-ENDO-2020-achondroplasia-poster-24-Apr-2020.pdf" target="_blank">Demuynck B et al</a>. Support for a new therapeutic approach of using a low-dose FGFR tyrosine kinase inhibitor (infigratinib) for achondroplasia. Approved by but not presented at ENDO 2020 due to COVID-19 pandemics. Acessed on 01-Jan-2021. <i>Open access.</i><br /></span></p><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;">7. </span><span style="font-family: Open Sans;"><span class="docsum-authors full-authors"><a href="https://academic.oup.com/endo/article/156/2/548/2422492" target="_blank">Matsushita M et al</a>.</span></span><span style="font-family: Open Sans;"><span class="docsum-authors full-authors"></span></span><span style="font-family: Open Sans;"> </span><span style="font-family: Open Sans;">Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.
<span class="docsum-journal-citation full-journal-citation">Endocrinology 2015; 156(2):548-54. </span></span><span style="font-family: Open Sans;"><span class="docsum-journal-citation full-journal-citation"><span style="font-family: Open Sans;"><i>Open access.</i></span></span></span></p><p><span style="font-family: Open Sans;">8. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229639" target="_blank"><span class="authors-list-item">Kitoh H</span></a><span class="period"><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229639" target="_blank"> et al</a>. </span>Pharmacokinetics and safety after once and twice a day doses of
meclizine hydrochloride administered to children with achondroplasia. PLoS ONE 2020<span class="cit">;15(4):e0229639. </span></span><span style="font-family: Open Sans;"><span class="docsum-journal-citation full-journal-citation"><span style="font-family: Open Sans;"><i>Open access.</i></span></span></span>
</p><span style="font-family: Open Sans;">9. <a href="https://www.sciencedirect.com/science/article/pii/S1525001616454535" target="_blank">Ling Jin et al.</a> Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain. Mol Ther 2016; 24 (11): 1974-1986. <i>Open access.</i><br /></span><p><span style="font-family: Open Sans;"></span></p><p><span style="font-family: Open Sans;">10. <a href="https://www.nature.com/articles/s41598-020-77345-y#Sec19" target="_blank">Ozaki T et al</a>. Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia.<span style="font-family: inherit;"> Sci Rep 2020; 10: 20915. <i>Open access</i>.</span></span></p><p><span style="font-family: Open Sans;"><span style="font-family: inherit;">11.</span></span><span style="font-family: Open Sans;"></span><span style="font-family: Open Sans;"><span style="font-family: inherit;"> </span><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680" target="_blank">Morozumi N et al</a>. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoSONE 2019;14(2):e0212680. </span><span style="font-family: Open Sans;"><span style="font-family: Open Sans;"><span style="font-family: inherit;"><i>Open access</i>.</span></span></span></p>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-19974122600277685552020-02-04T09:54:00.001-05:002020-11-01T20:34:08.248-05:00Tratando a acondroplasia: o papel das estatinas no tratamento da acondroplasia<div class="text-wrap tlid-copy-target">
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Estatinas restauram o crescimento ósseo em um modelo animal de acondroplasia</b></i><br /><br />Como muitos de vocês devem saber, há alguns anos um grupo japonês publicou um </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">elegante </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">trabalho mostrando que as estatinas, uma família de medicamentos amplamente usada para reduzir os níveis de colesterol, foram capazes de restaurar o crescimento ósseo em um modelo animal de acondroplasia (1). No entanto, os pesquisadores não conseguiram elucidar como esses medicamentos estavam funcionando em seu modelo. Posteriormente, o grupo liderado por Pavel Krejci publicou um estudo no qual descartavam qualquer ação direta das estatinas nas vias do <i>receptor do fator de crescimento de fibroblastos 3 </i>(FGFR3) (2).<br /><br />Agora, parece que o mecanismo pelo qual as estatinas poderiam restaurar ou promover o crescimento ósseo pode ter sido revelado, com a publicação de um novo estudo em que pesquisadores observaram que a fluvastatina, uma das estatinas, era capaz de aumentar a atividade de um eixo chave de enzimas que regulam positivamente o crescimento ósseo, a via IHH-PTHrP (IHH: Indian Hedgehog; PTHrP: peptídeo (ou proteína) relacionado ao hormônio da paratireóide) (3). Eu já havia revisto este estudo em detalhes em um artigo de outubro do ano passado.<br /><br />Isso parece complicado mas, em resumo, o crescimento ósseo é o resultado de um processo celular dentro de estruturas chamadas<i> placas de crescimento</i>, localizadas nas extremidades dos ossos longos (Figura 1). Lá, os condrócitos (as células mestres do crescimento ósseo), reagindo a muitos agentes, passam de um estado de repouso a um frenesi de alta proliferação e, finalmente, aumentam várias vezes de volume (ou tamanho) (Figura 1), dando espaço a novo tecido ósseo. É o ciclo celular</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"> contínuo</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"> de "despertar, proliferar, aumentar" do condrócito que alonga os ossos. Esse ciclo celular é fortemente regulado e a IHH e o FGFR3 são fundamentais para modular como os condrócitos se multiplicam e aumentam. O eixo IHH-PTHrP é especialmente importante no estágio de proliferação (4) e mutações no receptor PTHrP que prejudicam sua atividade normal causam uma displasia esquelética rara chamada <i>displasia metafisária de Jansen</i> (5), na qual os ossos estão severamente encurtados. Além disso, estudos anteriores mostraram que o FGFR3 reduz a atividade da via IHH-PTHrP (6) e que o PTH foi capaz de restaurar o crescimento em modelos de acondroplasia em camundongos (7,8).</span></span></div>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title="">Figura 1. Placa de crescimento.</span></span></span></span></div>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title=""> </span><br /> <br /><span title="">Quando em estado normal, o FGFR3 inibe a proliferação e a hipertrofia dos condrócitos </span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title="">por
meio de algumas cascatas enzimáticas no interior dos condrócitos, as
vias STAT1 e RAS-RAF-MEK-ERK (também chamada MAPK) (Figura 2</span> <span title="">),</span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title=""> em um nível que permite o crescimento ósseo equilibrado. </span><span title=""></span> <span title="">Na acondroplasia, devido à mutação em sua estrutura, o FGFR3 está trabalhando excessivamente, bloqueando bastante todo o processo de crescimento.</span> <span title="">Sob esse modelo, com a hiperatividade do FGFR3, menos condrócitos despertam do estado de repouso e menos proliferam e aumentam para permitir a construção de novo osso.</span><br /><br /><span title="">Figura 2. Vias ativadas pelo FGFR3 no condrócito.</span></span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span face=""trebuchet ms" , sans-serif"><span style="font-size: x-small;"><span class="tlid-translation translation" lang="pt"><span title="">Vias de sinalização ativadas por FGF/FGFR.</span> <span title="">FGFs induzem dimerização, ativação de quinase e transfosforilação de resíduos de tirosina de FGFRs, levando à ativação de vias de sinalização a jusante.</span> <span title="">Várias vias são estimuladas pela sinalização de FGF/FGFR, como as vias Ras-MAP quinase, PI-3 quinase/AKT e PLC-γ.</span> <span title="">Além disso, a sinalização de FGF também pode estimular a via STAT1/p21.</span> <span title="">A sinalização de FGF/FGFR também fosforila a proteína Shc e Src.</span> <span title="">FGF/FGFR desempenham papéis cruciais na regulação da proliferação, diferenciação e apoptose de condrócitos por vias de sinalização a jusante.</span> <span title="">De <a href="https://www.nature.com/articles/boneres20143">Su N et al.</a></span><a href="https://www.nature.com/articles/boneres20143"> </a><span title=""><a href="https://www.nature.com/articles/boneres20143">2014</a>. Reproduzido aqui apenas para fins educativos.</span></span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title=""><span class="tlid-translation translation" lang="pt"><i><b>Estratégias terapêuticas atuais</b></i><br /><br />Atualmente, existem quatro terapias para a acondroplasia em desenvolvimento clínico, explorando três estratégias diferentes. A mais avançada é um análogo do <i>peptídeo natriurético do tipo C</i> (CNP) chamado vosoritide (9). Outro análogo do CNP também está sendo testado (10). O CNP trabalha naturalmente contrabalançando os efeitos de uma das vias do FGFR3, chamada MAPK, que controla o ritmo da hipertrofia dos condrócitos, mas tem um efeito mínimo ou nulo na via do FGFR3 responsável por reduzir a proliferação dos condrócitos, de acordo com evidências publicadas até agora (11) (Figura 3). Existem vários artigos neste blog em que analisamos o CNP, basta visitar a página de índice para saber mais sobre ele.<br /><br />Figura 3. Estratégias terapêuticas para acondroplasia.</span></span></span></span></span></div>
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figura acima mostra os locais de ação do CNP, da meclizina e também dos
inibidores de tirosina quinase (TKI) NF449 e A31, que funcionam como o
infigratinib. De <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081569">Matsushita M et al. (2013)</a>. Reproduzido aqui apenas
para fins educacionais.</span></span></span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title=""><span class="tlid-translation translation" lang="pt">As outras duas estratégias visam diretamente o FGFR3, mas usando abordagens distintas. Um dos medicamentos, chamado <i>recifercept</i>, é de fato uma forma modificada de FGFR3 sem o gancho que normalmente ancora essa enzima na membrana celular dos condrócitos, permitindo que essa molécula circule livremente quando administrada (12). É por isso que é chamado de "receptor solúvel" (lembre-se de que o FGFR3 é uma enzima receptora). Então, como o recifercept funciona? Como você deve saber, o FGFR3 é um tipo de interruptor na parede dos condrócitos: ele precisa de um dedo (os FGFs, os ligantes) para ligar (ativar) e exercer suas funções (Figura 4). Ao circular livremente no corpo, o recifercept pode alcançar as placas de crescimento e capturar esses FGFs antes que eles ativem o FGFR3 (funciona fora da célula), explicando por que também é chamado de armadilha de ligantes (<i>ligand trap</i>, em inglês). A consequência é que, se o FGFR3 não estiver ativado, ele não poderá bloquear o ciclo celular do condrócito e o crescimento poderá ser restaurado (12). Aqui, você vê que o recifercept pode inibir todas as vias do FGFR3, portanto teria efeitos tanto nas fases de proliferação e hipertrofia dos condrócitos. Em teoria, seria mais potente que os análogos do CNP.</span></span></span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif"><span class="tlid-translation translation" lang="pt"><span title=""><span class="tlid-translation translation" lang="pt">Uma
ilustração da estratégia de armadilha de ligantes. O interruptor na
parede representa o FGFR3 e o dedo um ligante do FGFR (um FGF). O FGFR3 é
ativado quando um FGF se liga a ele. A armadilha (decoy ou trap) é feita de uma forma
"livre" de FGFR3, que compete com o interruptor da parede celular,
impedindo sua ativação.</span></span></span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span title=""><span class="tlid-translation translation" lang="pt"><br /><span id="goog_1980927825"></span><span id="goog_1980927826"></span>A terceira estratégia está sendo explorada com o infigratinib (13). Essa molécula é chamada i<i>nibidor da tirosina quinase</i> (TKI) e é capaz de se ligar a parte do FGFR3 responsável por ativar suas vias no interior do condrócito (Figura 3). Nesse caso, o FGFR3 continua sendo ativado fora da célula pelos FGFs, mas é incapaz de ativar suas vias dentro da célula. Isso significa que o infigratinib pode ser mais potente que os análogos do CNP, também afetando as duas fases principais do ciclo celular dos condrócitos.<br /><br /><br /><i><b>Como esses achados sobre as estatinas se encaixam no cenário terapêutico da acondroplasia?</b></i><br /><br />À medida que nosso entendimento de como as estatinas funcionam na placa de crescimento está avançando, podemos pensar em uma estratégia em que combiná-las com os análogos do CNP possa resultar em um efeito aprimorado no crescimento ósseo. Esse conceito também é aplicável à <i>meclizina</i>, que também atua inibindo a mesma via MAPK que o CNP inibe (14) (Figura 3). Por um lado, o CNP (ou meclizina) trabalharia para restaurar a capacidade dos condrócitos aumentarem e amadurecerem (hipertrofia), enquanto as estatinas atuariam para restaurar a atividade do eixo IHH-PTHrP, o que, por sua vez, ajudaria os condrócitos a recuperar sua capacidade de proliferação. para uma melhor resposta global do crescimento ósseo.<br /><br />No entanto, é claro que essa hipótese precisa ser testada em um modelo pré-clínico adequado como prova de conceito antes de qualquer etapa posterior. Por exemplo, alguém poderia pensar em um estudo com quatro braços: controle (placebo), somente CNP, somente estatina e CNP+estatina, o que permitiria aos pesquisadores determinar se haveria algum efeito sinérgico com essa combinação.<br /><br />As terapias combinadas também podem permitir uma redução das doses necessárias para alcançar os efeitos desejados no crescimento ósseo de cada um dos agentes sendo testados, reduzindo assim os riscos de efeitos indesejados. Por exemplo, um risco conhecido associado aos TKIs contra FGFRs usados no câncer é a hiperfosfatemia (15). Sabemos que a dose de infigratinib testada para acondroplasia é muito menor que a usada para o câncer (13), portanto o risco desse tipo de efeito colateral também seria menor, mas, e se a combinação com uma estatina pudesse reduzir ainda mais esse risco, permitindo uma dose ainda mais baixa do TKI?<br /><br />Como eu disse acima, modelos apropriados devem ser testados quanto à segurança e eficácia antes que qualquer uma dessas idéias possa avançar, mas o objetivo aqui é compartilhá-las e inspirar pesquisadores interessados em encontrar soluções para a acondroplasia e muitas outras displasias esqueléticas.</span></span></span></span><span style="font-size: small;"><br /> </span></span></div>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Se você segue este blog, é possível que você já saiba que as terapias para displasias relacionadas ao FGFR3 podem não apenas ser aplicáveis a vários outros tipos de displasias ósseas nas quais o FGFR3 desempenha um papel no mecanismo da doença, mas também em outras não relacionadas ao FGFR3, também. Um exemplo vem do desenvolvedor do vosoritide, que iniciou um programa para algumas formas de baixa estatura idiopática (veja mais informações <a href="https://investors.biomarin.com/download/BMRN_RDDay2019_111419_FINAL_11am.pdf">aqui </a>e <a href="https://investors.biomarin.com/download/JJMondayPresentation_BMRN_JPMorgan+_011120_FINAL.pdf">aqui</a>; em inglês; esses links levarão a duas apresentações em pdf. Nelas, basta procurar por acondroplasia. A primeira tem mais detalhes). Outro exemplo vem de um estudo com infigratinib, no qual os pesquisadores descobriram que a inibição do FGFR3 teve efeitos positivos em dois modelos animais de displasias graves associadas a mutações no gene <i>transportador de sulfato</i> (SLC26A2), que também causam a <i>displasia diastrófica</i> (16).<br /><br />As coisas estão melhorando e, embora resultados definitivos de todas as iniciativas em andamento e futuras ainda demorem alguns anos para serem disponibilizados, é reconfortante saber que, em um futuro não muito distante, muitas crianças serão poupadas de enfrentar as muitas complicações médicas que frequentemente ocorrem em displasias ósseas e terão melhor qualidade de vida.<br /><br />ps. Você pode encontrar muito mais informações sobre todas as estratégias revisadas brevemente aqui em outros artigos do blog. Visite a página de índice.<br /><br /><br /><i><b>Referências</b></i></span></span></div>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><br />1. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al</a>. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014; 513 (7519):507-11.<br /> <br /> 2. <a href="https://www.ncbi.nlm.nih.gov/pubmed/28583899">F</a><a href="https://www.ncbi.nlm.nih.gov/pubmed/28583899">afilek B et al</a>. Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage 2017; (9):1522-30.<br /> <br /> 3.<a href="https://www.ncbi.nlm.nih.gov/pubmed/31327238"> </a><a href="https://www.ncbi.nlm.nih.gov/pubmed/31327238">Ishikawa M et al</a>. The effects of fluvastatin on Indian Hedgehog pathway in endochondral ossification. Cartilage 2019; 22:1947603519862318. doi: 10.1177/1947603519862318. [Epub ahead of print]<br /> <br /> 4. <a href="https://www.ncbi.nlm.nih.gov/pubmed/12748651">Kronenberg HM</a>. Developmental regulation of the growth plate. Nature 2003; 423 (6937):332-6.<br /> <br /> 5. <a href="https://www.ncbi.nlm.nih.gov/pubmed/11021773">Calvi LM, Schipani E</a>. The PTH/PTHrP receptor in Jansen's metaphyseal chondrodysplasia. J Endocrinol Invest 2000;23(8):545-54.<br /><br /> 6. <a href="https://www.ncbi.nlm.nih.gov/pubmed/11181569">Chen L et al.</a> A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 2001; 10(5):457-65. <br /><br /> 7. <a href="https://www.ncbi.nlm.nih.gov/pubmed/17466614">Ueda K et al.</a> PTH has the potential to rescue disturbed bone growth in achondroplasia. Bone 2007;41(1):13-8. <br /><br /> 8. <a href="https://www.ncbi.nlm.nih.gov/pubmed/22634226">Xie Y et al. </a>Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. Hum Mol Genet 2012; 21(18):3941-55. <br /> <br />9. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31269546">Savarirayan R et al.</a> C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med 2019;381(1):25-35. <br /> <br />10. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31235532">Breinholt VM et al.</a> TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias. J Pharmacol Exp Ther 2019;370(3):459-71.<br /> <br /> 11.<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516592/"> Lorget F et al.</a> Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 2012;91(6):1108-14. <br /> Free access.<br /> <br /> 12. <a href="https://stm.sciencemag.org/content/5/203/203ra124.long">Garcia S et al.</a> Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 2013 Sep 18;5(203):203ra124. Free access.<br /><br />13. <a href="https://www.jci.org/articles/view/83926">Komla-Ebri D et al.</a> Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016;126(5):1871-84. Free access. <br /> <br />14. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081569">Matsushita M et al.</a> Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One. 2013 Dec 4;8(12):e81569. Free access.15. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714550/">Kelly CM et al.</a> A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor. Invest New Drugs 2019;37(2):282-90. Free access.<br /><br /> 15. <a href="https://ascopubs.org/doi/full/10.1200/JCO.2016.67.2048">Nogo</a><a href="https://www.ncbi.nlm.nih.gov/pubmed/27870574">va L et al.</a> Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol 2017;35(2):157-65. Free access.<br /> <br /> 16. <a href="https://www.sciencedirect.com/science/article/pii/S2352396419300106?via%3Dihub">Zheng C et al.</a> Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 2019;40:695-709. Free access.<span face=""trebuchet ms" , sans-serif"><span style="font-size: x-small;"> </span></span></span></span><br />
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Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-83821171088752717292020-02-03T14:34:00.003-05:002020-02-04T13:13:30.624-05:00Treating achondroplasia: statins' role for the treatment of achondroplasia<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i><b>Statins restore bone growth in an animal model of achondroplasia </b></i></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">As many of you may know, a few years ago a Japanese group published an elegant work showing that the <i>statins</i>, a family of drugs widely used to reduce cholesterol levels, were able to restore bone growth in an animal model of achondroplasia (1). However, the researchers were not able to find out how these medicines were working in their model. Later, the group leaded by Pavel Krejci published a study in which they ruled out any direct action of statins on the <i>fibroblast growth factor receptor 3</i> (FGFR3) pathways (2).</span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br />Now, it seems that the mechanism by which statins could restore or promote bone growth might have been unveiled, with the publication of a new study where researchers observed that fluvastatin, one of the statins, was able to increase the activity of a key enzyme axis that positively regulates bone growth, the IHH-PTHrP pathway (IHH: </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Indian Hedgehog; PTHrP: peptide (or protein) related to Parathyroid Hormone) (3)</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">.I have already reviewed it in an article from October last year.</span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br />This sounds complicated but in summary, bone growth is a consequence of a cell process within structures called growth plates that are located in the extremities of the long bones (Figure 1). There, the chondrocytes (the master cells of bone growth), reacting to many agents, go from a resting state to a highly proliferation frenzy and finally enlarge several times from their baseline size (Figure 1), then giving space to new bone tissue. It is the continuous chondrocyte's "awake, proliferate, enlarge" cell cycle that elongate bones. This cell cycle is tightly regulated and both </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">IHH and </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">FGFR3 are fundamental to modulate how chondrocytes multiply and enlarge. The IHH-PTHrP axis is specially important in the proliferation stage</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"> (4) and m</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">utations in the PTHrP receptor that impair its normal activity cause a rare skeletal dysplasia called </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i>Jansen metaphyseal dysplasia</i> (5) in which bones are severely shortened. Furthermore, previous studies showed that FGFR3 reduces the activity of the IHH-PTHrP pathway (6)</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">, and that PTH was able to restore growth in mouse models of achondroplasia (7,8). </span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Figure 1. Cartilage growth plate.</span></span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg6Q50Huje9_EF1BCE9rOIJBkK6IXDOdC3R8IEX5HLOqbEUdTr-pgmsVK3IBYnUTOfa1Rz1PN3mnN2rC4Zop-bGhFrNasbwKfTqmP9VellicUZXzBs6lFxF1wpxZ6tQ7K-w1kFi6B3jCgk/s1600/166_Growth_Plate_JPEG.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="254" data-original-width="400" height="404" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg6Q50Huje9_EF1BCE9rOIJBkK6IXDOdC3R8IEX5HLOqbEUdTr-pgmsVK3IBYnUTOfa1Rz1PN3mnN2rC4Zop-bGhFrNasbwKfTqmP9VellicUZXzBs6lFxF1wpxZ6tQ7K-w1kFi6B3jCgk/s640/166_Growth_Plate_JPEG.jpg" width="640" /></a></div>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"> </span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">In
normal state, FGFR3 inhibits both chondrocytes' proliferation and
hypertrophy to an extent that allows balanced bone growth through a couple of enzymatic cascades inside the chondrocyte, the STAT1 and the RAS-RAF-MEK-ERK (also called MAPK) pathways (Figure 2). In
achondroplasia, due to the mutation in its structure, FGFR3 is working
excessively, thus quite blocking the entire growth process. Under this model, upon the overactivity of FGFR3, fewer chondrocytes awake from the resting state and fewer will proliferate and enlarge to enable new bone to be built.</span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Figure 2. FGFR3 pathways.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhcj5PHrhtVstIH5c2Ve9_cOGgRsHghFsNBJiQo9av7BGTT5OsNOVavuNhcrNZcC_sXionuHPTiaSZ0Cq-gboL0Fk2a6V4WF3h62OKpES88f8H7KykN5IeIdpgTloRpg4pp7loVvSU3Vcc/s1600/FGFR3+cascade+2b.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="708" data-original-width="929" height="487" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhcj5PHrhtVstIH5c2Ve9_cOGgRsHghFsNBJiQo9av7BGTT5OsNOVavuNhcrNZcC_sXionuHPTiaSZ0Cq-gboL0Fk2a6V4WF3h62OKpES88f8H7KykN5IeIdpgTloRpg4pp7loVvSU3Vcc/s640/FGFR3+cascade+2b.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-family: "trebuchet ms" , sans-serif;">Signaling pathways activated by FGF/FGFR. FGFs induce dimerization,
kinase activation and transphosphorylation of tyrosine residues of
FGFRs, leading to activation of downstream signaling pathways. Multiple
pathways are stimulated by FGF/FGFR signaling such as Ras-MAP kinase,
PI-3 kinase/AKT and PLC-γ pathways. Furthermore, FGF signaling can also
stimulate STAT1/p21 pathway. FGF/FGFR signaling also phosphorylates the
Shc and Src protein. FGF/FGFR play crucial roles in the regulation of
proliferation, differentiation and apoptosis of chondrocytes via
downstream signaling pathways. <b>From <a href="https://www.nature.com/articles/boneres20143">Su N et al. 2014</a>. Reproduced here for educational purposes only.</b></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><b><i><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Current therapeutic strategies</span></span></i></b> </span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Currently,
there are four therapies for achondroplasia in clinical development
exploring three different strategies. The most advanced one is an
analogue of <i>C-type natriuretic peptide</i> (CNP) called <i>vosoritide</i> (9).
Another CNP analogue is also being tested (10). CNP works naturally
counteracting the effects of one of the FGFR3 pathways, called MAPK,
which controls the pace of chondrocytes' hypertrophy, but it has minimum
or no effect in the FGFR3 pathway responsible for reducing
chondrocytes' proliferation, according to the evidence so far (11) (Figure 3). There are several articles in this blog where we review CNP, you just have to browse the index page to learn more about it.</span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">Figure 3. <span style="font-size: small;">Therapeutic strategies for achondroplasia.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXg9teKJ2XDerLN03xaorq1RXuaF0Z5hHZGy20IKKVYSs_qHrovVDM7pn8v9jM2JjY2f9PTYESHwIGJXnB0oOgNxEyeE4MC-dtZxPz9RaEJM2XrpRpDYt3p5Gl_sTwyR3_WQWOBu7e-qo/s1600/Meclozine.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="600" data-original-width="514" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXg9teKJ2XDerLN03xaorq1RXuaF0Z5hHZGy20IKKVYSs_qHrovVDM7pn8v9jM2JjY2f9PTYESHwIGJXnB0oOgNxEyeE4MC-dtZxPz9RaEJM2XrpRpDYt3p5Gl_sTwyR3_WQWOBu7e-qo/s400/Meclozine.png" width="342" /></a></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;">The figure above shows the site of action of CNP, meclizine and also of the tyrosine kinase inhibitors (TKI) <a href="http://www.jbc.org/content/285/27/20644.full.pdf+html">NF449</a> and <a href="http://hmg.oxfordjournals.org/content/21/4/841.long">A31</a>, which work like infigratinib. From<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081569"> Matsushita M et al. (2013)</a><span style="color: black;">.</span><span style="color: black;"></span> Reproduced here for educational purposes only.</b></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">The other two strategies target FGFR3 </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">directly</span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">, but using distinct approaches. One of the drugs, called <i>recifercept</i>,
is in fact a modified form of FGFR3 lacking the hook which normally
anchors this enzyme to the chondrocyte cell membrane, allowing this molecule to circulate freely when administered (12). </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">That's why it is
called a <i>"soluble receptor"</i> (remember that FGFR3 is a receptor enzyme)</span></span>. So, how does it
work? As you may know, FGFR3 is a kind of power switch on the wall of
the chondrocytes: it needs a finger (the</span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> FGFs, the <i>ligands</i>)</span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> to turn on (activate) and exerts its
functions (Figure 4). By circulating freely in the body, recifercept can reach the growth plates and capture those FGFs before they engage FGFR3 (</span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">it works outside the cell)</span></span>, explaining why it is also called a <i>ligand trap.</i> The consequence is that if FGFR3 is not activated, then it cannot block the chondrocyte's cell cycle, and growth can be restored (12). Here, you see that recifercept might be able to inhibit all FGFR3 pathways, so would have effects both in the chondrocyte's proliferation and hipertrophy phases. In theory it would be more potent than CNP analogues.</span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Figure 4. Ligand trap.</span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2o1g71qV2YN0-BQ8wU1AXB5ak8S-2z9rYdcVa6tPq0He7ennqBcrRiufBIHZCAeEL6BZ2Zbh1dV2Oe0AnyooaZn5JkXcqOKi31X_bhXBuJw7KDu2yDVS98POU6ZgMbCgikkAiX8BR6kI/s1600/LigandTrap.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="375" data-original-width="1000" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg2o1g71qV2YN0-BQ8wU1AXB5ak8S-2z9rYdcVa6tPq0He7ennqBcrRiufBIHZCAeEL6BZ2Zbh1dV2Oe0AnyooaZn5JkXcqOKi31X_bhXBuJw7KDu2yDVS98POU6ZgMbCgikkAiX8BR6kI/s640/LigandTrap.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;">An illustration of the ligand trap strategy. The switch on the wall represents FGFR3 and the finger a FGFR ligand (a FGF). FGFR3 is activated when a FGF binds to it. The trap is made of a "free" form of FGFR3 which competes with the cell wall switch, preventing its activation.</span></span></td></tr>
</tbody></table>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">The third strategy is being explored with <i>infigratinib</i> (13). This molecule is called a<i> tyrosine kinase inhibitor </i>(TKI) and it is able to bind the part of FGFR3 which is responsible for activating its pathways inside the chondrocyte (Figure 3). In this case, FGFR3 keeps being activated outside the cell by the FGFs, but it is unable to turn on its pathways inside the cell. This means that infigratinib could be more potent than CNP analogues, </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">also having effects on both key chondrocyte's phases of the cell cycle.</span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i><b>How do those findings about the statins fit in the achondroplasia's therapeutic landscape ?</b></i></span></span></span> </span></span><br />
<br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">As our understanding of how statins work in the growth plate is advancing we could think on a strategy where combining them with CNP analogues may result in improved effect on bone growth. </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">This concept is also applicable to <i>meclizine</i>, which also works inhibiting the same MAPK pathway CNP does (14) (Figure 3).</span></span> By one side CNP (or meclizine) would work on restoring the ability of chondrocytes to enlarge and mature (hypertrophy) while statins would work restoring the activity of the IHH-PTHrP axis, which in turn would help chondrocytes to regain their proliferation capacity and leading to a better overall response on bone growth.</span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Nevertheless, it is clear that this hypothesis needs to be tested in an appropriate pre-clinical model as a proof of concept before any further step. For instance, one could think in a study with four arms: control (sham), CNP-only, statin-only and CNP-statin combo, which would allow researchers to determine if there were any sinergistic effects with that combination.</span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Combination therapies might also allow a reduction of doses needed to reach the desired effects on bone growth by each of the agents being tested, therefore reducing risks of undesired effects. For example, one known risk associated with TKIs against FGFRs used in cancer is </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">hyperphosphatemia (15). We know that the dose of infigratinib tested for achondroplasia is far lower than those used for cancer (13) so the risk of this kind of side effect would be also lower, but what if the combination with a statin could reduce that risk even more, by allowing an even lower dose of the TKI? </span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">As I said above, appropriate models must be tested for safety and efficacy before any of these ideas could be put in march, but the goal here is to share them and inspire researchers interested in finding solutions for achondroplasia and many other skeletal dysplasias. </span></span><br />
<br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">If you follow this blog it is possible that you already know that therapies for FGFR3-related dysplasias might not only be applicable for several other types of bone dysplasias where FGFR3 plays a role in the mechanism of disease, but also for other non FGFR3-related dysplasias as well. One example comes from the developer of vosoritide, which has started a program for some forms of idiopathic short stature (see more info <a href="https://investors.biomarin.com/download/BMRN_RDDay2019_111419_FINAL_11am.pdf">here </a>and <a href="https://investors.biomarin.com/download/JJMondayPresentation_BMRN_JPMorgan+_011120_FINAL.pdf">here</a>; these links will take you to two pdf presentations. You just have to browse them for achondroplasia. The first one has more details). Another example comes from a study with infigratinib in which the researchers found out that the inhibition of FGFR3 had positive effects in two animal models of severe dysplasias associated with mutations in the sulphate transporter gene, which is also the cause of diastrophic dysplasia (16). </span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /></span></span>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Things are getting better, and although definitive results from all the ongoing and upcoming initiatives will still take a few years to become available, it is reassuring that not in a distant future many children will be spared of enduring the many medical complications that often occur in bone dysplasias and will enjoy better quality-of-life.</span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br />ps. You can find much more information about all strategies briefly reviewed here in other articles of the blog. Try the index page. </span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i><b>References</b></i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">1.</span></span><span style="font-family: "trebuchet ms" , sans-serif;"> <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al</a>. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014; 513 (7519):507-11.<span style="font-size: small;"> </span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">2. <a href="https://www.ncbi.nlm.nih.gov/pubmed/28583899">F</a></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://www.ncbi.nlm.nih.gov/pubmed/28583899">afilek B et al</a>. Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage 2017; (9):1522-30.</span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;">3.</span><a href="https://www.ncbi.nlm.nih.gov/pubmed/31327238"> </a><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://www.ncbi.nlm.nih.gov/pubmed/31327238">Ishikawa M et al</a>. The effects of fluvastatin on Indian Hedgehog pathway in endochondral ossification. Cartilage 2019; 22:1947603519862318. doi: 10.1177/1947603519862318. [Epub ahead of print]</span> </span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">4. <a href="https://www.ncbi.nlm.nih.gov/pubmed/12748651">Kronenberg HM</a>. Developmental regulation of the growth plate. Nature 2003; 423(6937):332-6.</span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">5. <a href="https://www.ncbi.nlm.nih.gov/pubmed/11021773">Calvi LM, Schipani E</a>. The PTH/PTHrP receptor in Jansen's metaphyseal chondrodysplasia.<span class="jrnl" title="Journal of endocrinological investigation"> J Endocrinol Invest</span> 2000;23(8):545-54.</span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;">6. <a href="https://www.ncbi.nlm.nih.gov/pubmed/11181569">Chen L et al.</a>
A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in
mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia.
Hum Mol Genet 2001; 10(5):457-65.</span> </span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;">7. <a href="https://www.ncbi.nlm.nih.gov/pubmed/17466614">Ueda K et al.</a> PTH has the potential to rescue disturbed bone growth in achondroplasia. Bone 2007;41(1):13-8. </span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;">8.</span><span style="font-family: "trebuchet ms" , sans-serif;"> <a href="https://www.ncbi.nlm.nih.gov/pubmed/22634226">Xie Y et al. </a>Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. Hum Mol Genet 2012; 21(18):3941-55.</span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br />9. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><a href="https://www.ncbi.nlm.nih.gov/pubmed/31269546">Savarirayan R et al.</a> C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019;381(1):25-35. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><br />10. </span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://www.ncbi.nlm.nih.gov/pubmed/31235532">Breinholt VM et al.</a> TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3-Related Skeletal Dysplasias. J Pharmacol Exp Ther 2019 Sep;370(3):459-71.</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">11.<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516592/"> Lorget F et al.</a> Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012;91(6):1108-14. </span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i>Free access.</i></span></span> </span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">12. <a href="https://stm.sciencemag.org/content/5/203/203ra124.long">Garcia S et al.</a> Postnatal <b>soluble</b> <b>FGFR3</b> therapy rescues <b>achondroplasia</b> symptoms and restores bone growth in mice.<span class="jrnl" title="Science translational medicine"> Sci Transl Med</span>. 2013 Sep 18;5(203):203ra124. </span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i>Free access.</i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">13. </span><span style="font-size: small;"><a href="https://www.jci.org/articles/view/83926">Komla-Ebri D et al.</a>
Tyrosine kinase inhibitor NVP-BGJ398 functionally improves
FGFR3-related dwarfism in mouse model. J Clin Invest
2016;126(5):1871-84. <i>Free access.</i></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"> </span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">14. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081569">Matsushita M et al.</a> Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia. PLoS One. 2013 Dec 4;8(12):e81569.<i> Free access.</i></span><span style="font-family: "trebuchet ms" , sans-serif;">15.</span></span> <span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714550/">Kelly CM et al.</a> </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Invest New Drugs 2019;37(2):282-90. </span></span></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i>Free access.</i></span></span></span></span></span></span></div>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span><span style="font-size: small;"><br /></span><span style="font-size: small;">15.</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"> <a href="https://ascopubs.org/doi/full/10.1200/JCO.2016.67.2048">Nogo</a></span></span><span style="font-weight: normal;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="NLM_contrib-group"><span class="contribDegrees"><a href="https://www.ncbi.nlm.nih.gov/pubmed/27870574">va L et al.</a> </span></span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Evaluation of BGJ398, a Fibroblast Growth Factor Receptor
1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring
Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a
Global Phase I, Dose-Escalation and Dose-Expansion Study. </span></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="jrnl" title="Journal of clinical oncology : official journal of the American Society of Clinical Oncology">J Clin Oncol</span> 2017;35(2):157-65. <i>Free access.</i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">16. <a href="https://www.sciencedirect.com/science/article/pii/S2352396419300106?via%3Dihub">Zheng C et al.</a> Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 2019;40:695-709. <i>Free access</i>.</span></span><br />
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<br />Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-58859400266270746442020-01-29T08:33:00.002-05:002020-01-29T08:33:26.369-05:00Tratando a acondroplasia: oito anos online<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><i><b>Feliz Ano Novo!</b></i><br /><br />O blog Tratando a Acondroplasia está fazendo oito anos online e já recebeu mais de 380 mil visitas de mais de 160 países. Esta tem sido uma jornada e tanto. Novos visitantes podem não saber, mas tudo começou depois que passei algum tempo conversando com pesquisadores, experts e representantes de associações de pacientes em 2009 e 2010, tentando entender seus pontos de vista sobre a acondroplasia. Percebi que havia lacunas no conhecimento e uma espécie de desconexão entre a comunidade científica e os pais e famílias. Embora houvesse pesquisa sendo realizada naquele momento, a comunidade interessada tinha muito pouco acesso a ela, ou porque não era fácil filtrar as informações relevantes ou porque essas informações relevantes eram divulgadas em linguagem científica, não acessível a todos. Assim, o blog começou com a idéia de traduzir essa linguagem científica daqueles estudos em um texto que pudesse ajudar o leitor leigo a entender o que era acondroplasia e o que estava sendo feito para tentar corrigir o comprometimento do crescimento causado pela mutação no gene do <i>receptor</i></span></span><i><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> de fator de crescimento</span></span></i><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><i> de fibroblasto 3 </i>(FGFR3).<br /><br />Desde então, muitas estratégias terapêuticas foram exploradas, como você pode ver navegando na página de índice do blog. Algumas delas alcançaram o estágio de desenvolvimento clínico, e a mais avançada, o vosoritide, um análogo do <i>peptídeo natriurético tipo C</i> (CNP), está mais próximo de chegar ao mercado, de acordo com seu desenvolvedor, Biomarin.<br /><br />Lembre-se de que você sempre pode procurar outros artigos do blog para obter informações mais detalhadas sobre a acondroplasia e os mecanismos de ação dos medicamentos que mencionamos brevemente aqui.<br /><br />Então, vamos ver com mais detalhes o que aconteceu em 2019 com a pesquisa de terapias para a acondroplasia. Abaixo, você verá um breve resumo das quatro moléculas em teste no momento.<br /><br /><i><b>Vosoritide - Biomarin</b></i><br /><br />O desenvolvedor anunciou recentemente seus planos de submeter os resultados do estudo de fase 3 com vosoritide ao FDA em 2020, esperando receber aprovação em 2021 para crianças acima de 6 anos. Eles também divulgaram mais dados sobre o estudo de extensão de longo prazo com os participantes do estudo da fase 2. No estudo da fase 3, descobrimos que, em comparação com o placebo, o vosoritide melhorou a velocidade de crescimento em 1,9 cm em um ano, em média. Os resultados do estudo de fase 2 revelaram que o efeito no crescimento parece ser sustentado ao longo dos anos. Além disso, eles também anunciaram que as duas primeiras coortes do estudo de fase 2 com bebês e crianças de até cinco anos de idade estão totalmente recrutadas e que a terceira coorte de bebês está em andamento no momento em que estou escrevendo este artigo. </span></span><br />
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br />Para saber mais sobre o status e os planos do vosoritide, clique no link a seguir que o levará à apresentação </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">da Biomarin</span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> no evento do JP Morgan, ocorrido no início deste mês.</span></span><br />
<ul>
<li><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> <a href="https://investors.biomarin.com/download/JJMondayPresentation_BMRN_JPMorgan+_011120_FINAL.pdf">Apresentação da Biomarin no evento JP Morgan</a></span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">(em inglês)</span></span> </span></span><br /><span style="font-family: "Trebuchet MS", sans-serif;"></span></li>
</ul>
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br /><i><b>TransCon CNP - Ascendis Pharma</b></i><br /><br />Seguindo os passos da Biomarin, a Ascendis iniciou o recrutamento de voluntários para o estudo de história natural, que é um requisito para se inscrever no estudo de intervenção medicamentosa com seu próprio análogo do CNP. Parece que eles também conseguiram iniciar o recrutamento do estudo de fase 2 com o TransCon-CNP. No ano passado, eles também publicaram os resultados de seus estudos pré-clínicos e divulgaram informações sobre o estudo da fase 1 em voluntários saudáveis. A principal diferença entre o TransCon-CNP e o vosoritide é que ele foi projetado para ser administrado uma vez por semana em comparação com o produto da Biomarin, que é administrado em uma injeção diária. Os interessados em participar dos ensaios da Ascendis podem visitar esses links para obter mais informações:</span></span><br />
<ul>
<li><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> <a href="https://www.clinicaltrials.gov/ct2/show/NCT03875534?term=achondroplasia&recrs=abdf&draw=2&rank=2">Estudo de história natural </a></span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">(em inglês)</span></span> </span></span></li>
<li><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> <a href="https://www.clinicaltrials.gov/ct2/show/NCT04085523?term=achondroplasia&recrs=abdf&draw=2&rank=6">Estudo de fase 2</a></span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">(em inglês)</span></span> </span></span><br /><span style="font-family: "Trebuchet MS", sans-serif;"></span></li>
</ul>
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br /><i><b>Recifercept (TA-46) - Pfizer</b></i><br /><br />Therachon, o desenvolvedor original do TA-46, passou a bola para a Pfizer, após a divulgação dos resultados dos testes da fase 1. A molécula recebeu então o nome de <i>recifercept</i>. Este medicamento é chamado de "armadilha de ligante" e foi projetado para capturar os agentes que normalmente ativam o FGFR3 antes que possam ativar o receptor mutado. Se o FGFR3 permanecer inativo, o crescimento ósseo poderá ser restaurado. A Pfizer também iniciou o estudo de história natural que permitirá aos voluntários ingressar no estudo da fase 2 posteriormente. O link a seguir levará você a mais informações sobre o estudo de história natural:</span></span><br />
<ul>
<li><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> <a href="https://www.clinicaltrials.gov/ct2/show/NCT03794609?term=achondroplasia&recrs=abdf&draw=2&rank=5">Estudo de história natural</a></span></span> <span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">(em inglês)</span></span> </li>
</ul>
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><i><b><br />Infigratinib (BGJ-398) - QED</b></i><br /><br />O desenvolvedor do infigratinib, uma molécula projetada para bloquear as vias intracelulares dos FGFRs, também iniciou seu estudo de história natural. Não sei se eles já começaram o estudo de fase 2. Essa droga funcionaria "cortando" os fios que acionam as reações químicas desencadeadas pelo FGFR3, deixando os condrócitos retomar o processo de crescimento ósseo. Para saber mais sobre o estudo de história natural:</span></span><br />
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<li><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> <a href="https://www.clinicaltrials.gov/ct2/show/NCT04035811?term=achondroplasia&recrs=abdf&draw=2&rank=7">Estudo de História Natural</a></span></span></li>
</ul>
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<i><b><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">Mais novidades</span></span></b></i><br />
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br />Outras terapias experimentais foram reportadas recentemente, incluindo um terceiro análogo do CNP por um desenvolvedor japonês, mas elas ainda estão longe do desenvolvimento clínico. Outras perspectivas positivas vêm de estudos usando o CNP e outras drogas para modular as atividades do FGFR3 em displasias esqueléticas onde o FGFR3 não sofre mutação mas ainda desempenha um papel relevante no comprometimento do crescimento ósseo observado nesses distúrbios. Essas são notícias animadoras, uma vez que disponibilizar terapias para distúrbios como a displasia disastrófica e as RASopatias pode ajudar a melhorar a qualidade de vida de crianças afetadas por mutações nos respectivos genes causadores.<br /><br />As coisas estão melhorando e esperamos assistir a mais novidades em 2020, trazendo novas esperanças e soluções para a acondroplasia e muitas outras displasias esqueléticas.</span></span>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-2148176063614317562020-01-28T14:07:00.001-05:002020-01-29T08:35:06.860-05:00Treating Achondroplasia: eight years online<i><b><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Happy New Year! </span></span></b></i><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">The Treating Achondroplasia blog is reaching eight years online and it has now received more than 380K visits from more than 160 countries. This has been quite a journey. New visitors may not know but it all started after I spent sometime talking with investigators, researchers and representatives from advocacy groups back in 2009 and 2010, trying to understand their points-of-view over achondroplasia. I realized that there were gaps on knowledge and a kind of disconnect between the scientific community and parents and families. Although there was research being pursued at that time, the interested community had very little access to it, either because it was not easy to filter the relevant information, or because that relevant information was delivered in hard jargon, not accessible to all. So, the blog started with the idea of translating the deep science language from those studies to a text that could help the lay reader to understand what was achondroplasia and what was being done to try to correct the growth impairment caused by the mutation in the <i>fibroblast growth factor receptor 3</i> (<i>FGFR3</i>) gene.</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Since that time, many therapeutic strategies have been explored, as you can see browsing the blog's index page. Some of them have been successfully moved to clinical development, and the more advanced one, <i>vosoritide</i>, a <i>C-type natriuretic peptide</i> (CNP) analogue, is closer to reach the market, according with its developer, Biomarin.</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Remember that you can always browse other articles of the blog to get more detailed info about achondroplasia and the mechanisms of action of the drugs we briefly mention here.</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">So, let's see with more detail what happened in 2019 with the research for therapies for achondroplasia. Below you will see a brief summary of the four molecules under test right now.</span></span><br />
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<i><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><b>Vosoritide - Biomarin</b></span></span></i><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">The developer recently announced their plans to submit the results of the phase 3 study with vosoritide to the FDA during 2020, expecting to receive approval in 2021 for children over 6 years old. They also released more data on the long term extension study with participants from the phase 2 study. From the phase 3 study we learned that compared to placebo, vosoritide improved growth velocity by 1.9 cm in one year on average. The results from the phase 2 study revealed that the effect on growth seems to be sustained throughout the years. Furthermore, they also announced that the first two cohorts of the phase 2 study with infants and toddlers, of children 5 year-old or less, are fully recruited, and that the third cohort in infants is in progress at the moment I am writing this text.</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">To learn more about Biomarin's vosoritide status and plans, click on the following link that will lead you to their presentation at the JP Morgan event earlier given earlier this month.</span></span><br />
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<li><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://investors.biomarin.com/download/JJMondayPresentation_BMRN_JPMorgan+_011120_FINAL.pdf">Biomarin's presentation at the JP Morgan event</a><i><span style="font-size: small;"><b> </b></span></i></span></li>
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<i><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><b>TransCon CNP - Ascendis Pharma</b></span></span></i><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Following the steps of Biomarin, Ascendis started the recruitment of volunteers for their natural history study, which is a requirement to enroll in the drug intervention study with their own CNP analogue. It seems that they have been able to start the recruitment of their phase 2 study with TransCon-CNP as well. Last year, they have also published the results of their pre-clinical studies and released information about the phase 1 study in healthy volunteers.The main difference between this asset and vosoritide is that it has been designed to be given once a week compared with the Biomarin's product, which is given in a daily injection. Those interested in joining Ascendis' trials could visit these links for more information:</span></span><br />
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<li><a href="https://www.clinicaltrials.gov/ct2/show/NCT03875534?term=achondroplasia&recrs=abdf&draw=2&rank=2"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Natural history study</span></span></a></li>
<li><a href="https://www.clinicaltrials.gov/ct2/show/NCT04085523?term=achondroplasia&recrs=abdf&draw=2&rank=6"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Phase 2 study</span></span></a></li>
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<i><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><b>Recifercept (TA-46) - Pfizer</b></span></span></i><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Therachon, the original developer of TA-46, passed the ball to Pfizer, after the release of their phase 1 trial results. The molecule was then named recifercept. This drug is called a "ligand trap" and it was designed to capture the agents that normally activate FGFR3 before they are able to activate the mutated receptor. If FGFR3 remains inactive then growth can be restored. Pfizer has also started the natural history study that will allow volunteers to join the phase 2 study later. The following link will take you to more information about their natural history study:</span></span><br />
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<li><a href="https://www.clinicaltrials.gov/ct2/show/NCT03794609?term=achondroplasia&recrs=abdf&draw=2&rank=5"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Natural history study</span></span></a><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"> </span></span></li>
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<i><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><b>Infigratinib (BGJ-398) - QED</b></span></span></i><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">The developer of infigratinib, a molecule designed to block FGFRs' intracellular pathways, has also started their natural history study. I am not aware if they have started their phase 2 study yet. This drug would work by "cutting" the wires that drive the chemical reactions elicited by FGFR3, leaving the chondrocytes able to resume their growth process. To learn more about their natural history study:</span></span><br />
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<li><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://www.clinicaltrials.gov/ct2/show/NCT04035811?term=achondroplasia&recrs=abdf&draw=2&rank=7">Natural History study</a> </span></span></li>
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<i><b><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">More news</span></span></b></i><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Other experimental therapies have been reported lately, including a third CNP analogue by a Japanese developer, but they are still far away from clinical development now. Other positive perspectives come from studies using CNP and other drugs to modulate FGFR3 activities in skeletal dysplasias where FGFR3 is not mutated but still plays a relevant role in the bone growth impairment seen in those disorders. These are reassuring news since making available therapies for disorders such as dyastrophic dysplasias and RASopathies may help improving the quality of life of children affected by mutations in the respective causative genes.</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Things are only getting better and we hope we will watch more news during 2020 bringing new hope and solutions for achondroplasia and many other skeletal dysplasias. </span></span><br />
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<br />Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-85738706115802459692019-11-13T14:13:00.002-05:002019-12-05T08:11:41.942-05:00Tratando a acondroplasia: como aperfeiçoar o tratamento da acondroplasia<div class="separator" style="clear: both; text-align: center;">
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A conferência contou com especialistas clínicos e cientistas de todo o mundo.<br /><br />Dado meu envolvimento com a acondroplasia, tenho minhas próprias percepções sobre os altos e baixos do atendimento, mas eu queria ter uma visão mais ampla que pudesse apresentar aos outros especialistas durante minha palestra. Como eu queria ouvir as famílias e as pessoas que lidam diretamente com questões de saúde, iniciei uma pequena pesquisa em três grupos ligados à acondroplasia no Facebook (Fb; dois internacionais e um do Brasil). A pesquisa não foi para calcular taxas disso e daquilo, mas para entender a visão das pessoas sobre os cuidados de saúde relacionados à acondroplasia.<br /><br />Em resumo, o objetivo da pesquisa era reunir impressões sobre o que funciona bem e o que não funciona quando alguém precisa de assistência médica ou suporte do sistema de saúde. Extraí o feedback recebido dos membros dos grupos do Fb de diferentes países ao redor do mundo e os acrescentei à apresentação, além de adicionar testemunhos reais coletados de vários outros grupos. Todas as informações que poderiam levar à identificação pessoal foram editadas. Mais do que dar minha opinião, a maneira como apresentei os dados tinha um único objetivo: fornecer aos especialistas da conferência pontos de vista sobre cuidados de saúde que não são frequentemente compartilhados com eles em sua prática diária.<br /><br />Obviamente, a mensagem, ou mensagens, oferecidas durante aquela apresentação estão longe de abordar todos os aspectos envolvidos no tratamento e apoio que indivíduos com acondroplasia e suas famílias precisam e merecem. Minha palestra enfatizou basicamente uma questão importante que as pessoas de todo o mundo enfrentam quando procuram assistência médica e / ou apoio. No entanto, acredito que o que mostrei foi capaz de mover a audiência na direção certa. Prometi publicar os resultados da pesquisa, e é o que estou fazendo agora, compartilhando com vocês a apresentação que fiz e sou muito grato a todos os membros que forneceram suas opiniões e idéias. Obrigado!</span></span><br />
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Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-64733101274591721802019-11-13T13:45:00.000-05:002019-11-13T13:59:27.273-05:00Treating Achondroplasia: how to improve the healthcare for achondroplasia<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i><b>A conference and a survey</b></i> <br /><br />A few months ago I was invited to speak at a conference about how the community sees the healthcare and general support for achondroplasia. The conference had clinical and scientific experts from all over the world. <br /><br />Given my involvement with achondroplasia, I have my own perceptions about the ups and downs of care, but I wanted to have a broader view that I could present to the other experts during my talk. I wanted to hear from families and people who deal directly with health issues, so I started a short survey in three achondroplasia-related groups in Facebook (Fb; two international and one based in Brazil). The survey was not about calculating rates of this and that, but to understand people's view about the healthcare for achondroplasia.<br /><br />In summary, the purpose of the survey was to gather impressions of what works well and what doesn't when someone needs healthcare or support from the healthcare system. I have extracted the feedback received from Fb group members from different countries around the world and collated them, and also added real testimonies collected from Fb groups. All information that could lead to personal identification was redacted. More than giving my own opinion, the way I presented the data had one single goal, which was to provide the experts in the conference with points-of-view about healthcare that are not frequently shared with them in their daily practice. <br /> <br />Of course, the message, or messages, given during that presentation are far from approaching all aspects involved in the care and support individuals with achondroplasia and their families need and deserve. My talk basically emphasized an important issue people all over the world face when seeking for healthcare and/or support. However, I believe that what I showed was able to move the audience towards the right direction. I promised to publish the results of the survey, which is what I am doing now, by sharing with you the presentation I gave and I am really grateful to all those members that provided their opinions and insights. Thank you!</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"></span></span><br />
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Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-6412334400031683692019-10-08T14:14:00.001-04:002019-10-08T14:14:11.966-04:00Tratando a acondroplasia: desvendando o mecanismo de ação das estatinas no crescimento ósseo<div class="text-wrap tlid-copy-target">
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<span class="tlid-translation translation" lang="pt"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i><b>Introdução</b></i><br /><br />O texto abaixo pode parecer muito técnico, mas você pode ler mais sobre o básico em outros artigos deste blog. Você só precisa ir até a página de índice no seu idioma preferido (inglês, espanhol ou português; veja a barra no topo desta página) para encontrar mais informações sobre tudo o que é discutido aqui, como a placa de crescimento e as estatinas. Também adicionei vários links para esses artigos ao longo do texto.<br /><br /><i><b>Qual o papel do FGFR3 no crescimento ósseo?</b></i><br /><br />O crescimento ósseo é um processo rigidamente controlado que ocorre dentro de estreitas camadas de cartilagem localizadas nas extremidades dos ossos longos das crianças, as placas de crescimento. As células responsáveis pelo crescimento ósseo nas placas de crescimento são chamadas de condrócitos (Figura 1) (1).</span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br /><br />Figura 1. Estrutura da placa de crescimento cartilaginosa.</span></span></span><br />
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<span class="tlid-translation translation" lang="pt"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br /></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Como sabemos, o receptor de fator de crescimento de fibroblastos 3 (FGFR3) ajuda a modular o ciclo celular dos condrócitos na placa de crescimento por duas vias químicas principais, uma definida por um grupo de enzimas chamadas MAPK e a outra por sua principal enzima, a STAT1. Enquanto a STAT1 controla o ritmo de multiplicação (proliferação) da célula, a via MAPK é um controlador-chave do ritmo de diferenciação de condrócitos (hipertrofia) (Figura 2) (1). O FGFR3, trabalhando por essas vias, inibe o crescimento ósseo.</span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br /><br />Figura 2. Vias do FGFR3.</span></span></span><br />
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<tr align="justify"><td class="tr-caption"><span style="font-family: "Trebuchet MS", sans-serif;"><span class="tlid-translation translation" lang="pt"><span class="" title="">Vias de sinalização ativadas pelo FGF/FGFR.</span> <span title="">FGFs induzem dimerização, ativação de quinase e transfosforilação de resíduos de tirosina de FGFRs, levando à ativação de vias de sinalização a jusante.</span> <span title="">Várias vias são estimuladas pela sinalização de FGF/FGFR, como as vias Ras-MAP quinase (MAPK), PI3K/AKT e PLC-γ.</span> <span title="">Além disso, a sinalização do FGF também pode estimular a via STAT1/p21.</span> <span title="">A sinalização do FGF/FGFR também fosforila a proteína Shc e Src.</span> <span title="">FGF/FGFR desempenham papéis cruciais na regulação da proliferação, diferenciação e apoptose de condrócitos por vias de sinalização a jusante.</span> <span title="">De Su N et al., Bone Res.</span> <span title="">2014 (2).</span> <span title="">Reproduzido aqui apenas para fins educacionais.</span></span></span></td></tr>
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<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br />Não se preocupe com a complexidade aqui, visite o <a href="https://tratando-acondroplasia.blogspot.com/p/glossario-aminoacidos-moleculas-com.html">glossário </a>do blog para obter uma breve descrição da placa de crescimento e de suas camadas. Outros artigos do blog também contêm descrições mais detalhadas da placa de crescimento (você pode tentar <a href="https://tratando-acondroplasia.blogspot.com/2019/06/tratando-acondroplasia-o-cnp-no-centro.html">este</a>).<br /><br />Estatinas para a acondroplasia? </span></span><br />
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<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">As estatinas estão sob os holofotes desde 2014, quando um grupo japonês publicou um </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">elegante </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">estudo explorando o uso de estatinas para a acondroplasia: eles descobriram que as estatinas eram capazes de resgatar o crescimento ósseo em um modelo de acondroplasia (você pode ler mais <a href="http://tratando-acondroplasia.blogspot.com.br/2014/12/tratando-acondroplasia-com-estatinas.html">aqui</a>) (3 ). No entanto, eles não conseguiram elucidar como esses medicamentos teriam funcionado (seu mecanismo de ação). Posteriormente, o grupo tcheco liderado pelo <a href="https://www.achondroplasia-registry.cz/index-en.php">Dr. Pavel Krejci</a> publicou um estudo em que descartou qualquer efeito direto das estatinas no FGFR3 (4), mantendo a questão de como as estatinas poderiam ter resgatado o crescimento ósseo naquele estudo original sem uma resposta apropriada.<br /><br />Pensando em soluções terapêuticas para acondroplasia </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">as estatinas </span></span>podem se tornar uma solução útil: são baratas, têm um perfil de segurança conhecido e têm sido amplamente utilizadas em várias indicações clínicas, inclusive em crianças e mulheres grávidas. Leia mais sobre as estatinas <a href="https://tratando-acondroplasia.blogspot.com/2018/05/tratando-acondroplasia-uma-revisao-do.html">aqui</a>.<br /><br /><i><b>Se as estatinas não bloqueiam o FGFR3, como elas resgatam o crescimento ósseo?</b></i></span></span><br />
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<li><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> As estatinas restauram a proliferação de condrócitos</span></span></li>
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<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">Um estudo muito recente publicado por outro grupo japonês parece finalmente ter revelado o mecanismo de ação desses medicamentos, explicando como as estatinas podem induzir o crescimento ósseo na acondroplasia.<br /><br />Ishikawa et al. (5) descobriram que a fluvastatina, uma das estatinas, foi capaz de aumentar a expressão de um dos principais reguladores do crescimento ósseo, uma proteína chamada<i> Indian Hedgehog</i> (IHH). A IHH, por sua vez, induz a liberação </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">local </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">de um peptídeo na placa de crescimento chamado <i>peptídeo relacionado ao hormônio da paratireóide</i> (PTHrP). Quando o PTHrP é liberado na placa de crescimento, estimula os condrócitos a permanecerem em um estado proliferativo (1), retardando sua transição para o estado hipertrófico. Este <a href="http://tratando-acondroplasia.blogspot.com.br/2012/07/paratormonio-para-tratar-acondroplasia.html">artigo </a>do blog tem mais informações sobre as atividades do eixo IHH-PTHrP na placa de crescimento.<br /><br />Portanto, tanto o IHH quanto o PTHrP são promotores de crescimento ósseo, em contraste com o FGFR3, que funciona naturalmente como um freio de crescimento na placa de crescimento.<br /><br /><i><b>Existe alguma correlação entre o FGFR3 e a IHH?</b></i><br /><br />Em 2001, Chen et al. (6) demonstraram que o FGFR3 causava um efeito inibitório direto no eixo IHH-PTHrP na placa de crescimento (Figura 3). O mecanismo exato pelo qual o FGFR3 inibe a IHH e a PTHrP ainda não está claro, embora pareça que uma das vias químicas ativadas através do FGFR3 (a via STAT1 - Figura 2) induz inibidores do ciclo celular (agentes que bloqueiam a multiplicação celular), levando à inibição da IHH (que é, como dito acima, um promotor de proliferação celular).<br /><br />Figura 3. Correlação entre o FGFR3 e a IHH na placa de crescimento. </span></span><br />
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<tr align="justify"><td class="tr-caption"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: x-small;">Modelo das relações entre FGF-FGFR3 e a sinalização IHH-PTHrP-PTHrP-R na formação óssea endocondral.
Os sinais FGF-FGFR3 e IHH-PTHrP-PTHrP-R são transmitidos por duas vias
paralelas integradas que mediam funções sobrepostas e distintas durante o
crescimento de ossos longos. Tanto o FGFR3 quanto o IHH afetam a proliferação de condrócitos. No entanto, o FGFR3 é um regulador negativo do crescimento ósseo, enquanto o IHH regula positivamente o crescimento ósseo.
As evidências sugerem que a sinalização de FGF-FGFR3 induz a ativação de
proteínas STAT, a regulação positiva da expressão de inibidores do
ciclo celular e a regulação negativa da expressão de IHH. Os sinais
FGF-FGFR3 e PTHrP-PTHrP-R inibem a diferenciação de condrócitos, e ambos
os sinais parecem atuar de maneira dominante e independente. De Chen L et al. Hum Mol Gen 2001; 10 (5): 457-65 (6). Reproduzido aqui apenas para fins educacionais.</span></span></td></tr>
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<br /><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt">Então, em resumo, Ishikawa et al. descobriram que as estatinas parecem restaurar o eixo IHH-PTHrP nos condrócitos afetados pela sinalização do FGFR3, melhorando a capacidade de proliferação dessas células.<br /><br /><i><b>Por que esse achado é importante?</b></i><br /><br />Como vimos acima, o FGFR3 inibe o crescimento ósseo, reduzindo a taxa de proliferação de condrócitos e sua capacidade de diferenciar e crescer (amadurecer, um processo chamado hipertrofia). Esses dois estágios dos condrócitos representam o núcleo do processo de crescimento ósseo.<br /><br />Para colocar essas informações em contexto e ajudar os leitores a entender sua relevância, é importante saber que a </span></span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt">atual </span></span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt">terapia potencial mais avançada para a acondroplasia, o vosoritide, que é um análogo do peptídeo natriurético do tipo C (CNP), funciona especificamente sobre a via MAPK, portanto, resgata apenas um dos principais processos regulados pelo FGFR3 (7).<br /><br />Nesse contexto, é possível que estratégias que visem inibir diretamente a atividade do FGFR3 possam proporcionar melhores resultados em termos de resgate do crescimento ósseo, pois afetariam as duas principais vias desencadeadas por esse receptor (Figura 2). Este é o caso do recifercept (TA-46) e do infigratinib (BGJ-398) (confira os artigos no blog que revisam essas moléculas).<br /><br />Em conclusão, os dados fornecidos por Ishikawa et al. podem servir como base para os pesquisadores explorarem a combinação de terapias direcionadas à via MAPK - todas as terapias baseadas no CNP, inibidores anti-MAPK quinase e meclizina - com estatinas, aproveitando seus mecanismos exclusivos de ação. Essas combinações poderiam funcionar em sinergia para resgatar o crescimento ósseo na acondroplasia e em outras displasias esqueléticas nas quais a atividade excessiva do FGFR3 desempenha um papel relevante.<br /><br /><i><b>Referências</b></i></span></span></span><br /><br /><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">1. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579395/#">Long F, Ornitz DM</a>. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 2013;5(1):a008334. Acesso gratuito.<br /> <br />2. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472122/"> Su N et al.</a> Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2014;2:14003. </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">Acesso gratuito.</span></span></span></span><br />
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<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">3. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al.</a> Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014 ;513(7519):507-11. <br /><br /> 4. <a href="https://www.oarsijournal.com/article/S1063-4584(17)31024-5/fulltext">Fafilek B et al.</a> Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage. 2017 Sep;25(9):1522-1530. </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">Acesso gratuito.</span></span></span></span></span></span><br />
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"> </span></span></span></span><br /> 5. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31327238">Ishikawa M et al</a>. The effects of fluvastatin on indian hedgehog pathway in endochondral ossification. Cartilage. 2019 Jul 22:1947603519862318. <br /><br /> 6. <a href="https://academic.oup.com/hmg/article/10/5/457/2901553">Chen L et al.</a> A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 2001; 10(5):457-65. </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">Acesso gratuito.</span></span></span></span></span></span><br />
<span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><br /> 7. <a href="https://www.cell.com/ajhg/fulltext/S0002-9297(12)00537-X">Lorget F et al.</a> Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012 ;91(6):1108-14. </span></span><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span style="font-size: small;">Acesso gratuito.</span></span></span></span> <br /><br /> <br /><br /> </span></span><br /> </div>
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Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-57950769746384212822019-10-06T20:18:00.004-04:002019-10-21T14:22:05.861-04:00Treating achondroplasia: unveiling the mechanism of action of statins on bone growth<div data-contents="true">
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i><b>Introduction </b></i><br /><br /> The text below could look very technical, but you can read more about the basics in other articles of this blog. You just need to go to the index page in your preferred language (English, Spanish or Portuguese; see the bar on top of this page) to find out more information about everything discussed here, such as the growth plate and statins. I have also added several links to those articles throughout the text. </span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i><b><span style="font-family: "trebuchet ms" , sans-serif;">What's the role of FGFR3 in bone growth?</span></b></i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">Bone
growth is a tightly controlled process that takes place within thin
layers of cartilage located in the extremities of children's long bones,
the growth plates. The cells responsible for the bone growth in the
growth plates are called chondrocytes (Figure 1) (1).</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">Figure 1. Cartilage growth plate structure.</span></span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiNd5Kmvs1Ny_4FduVi9s3WvLhVf_6RuUl69oJoncqOLvAZB39jStzitAckbh-3a23wAfXqQm3U51XpvGngzip3e3Ns3w02Re0PakJp_eOUyrji5wEwCa5KjZ-dgJFg1zHUDpNJM_AzZFM/s1600/GrowthPlate04.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="381" data-original-width="600" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiNd5Kmvs1Ny_4FduVi9s3WvLhVf_6RuUl69oJoncqOLvAZB39jStzitAckbh-3a23wAfXqQm3U51XpvGngzip3e3Ns3w02Re0PakJp_eOUyrji5wEwCa5KjZ-dgJFg1zHUDpNJM_AzZFM/s1600/GrowthPlate04.jpg" /></a></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">As
we know, </span><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="bi5kl-0-0"><span data-text="true"><span style="font-size: small;"><i>fibroblast growth factor receptor 3</i> </span>(</span></span></span></span>FGFR3) helps modulating the chondrocyte cell cycle within the
growth plate through two main chemical pathways, one managed by a group
of enzymes called MAPK and the other defined by its main enzyme STAT1. </span><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">While STAT1 controls the cell's multiplication (<b>proliferation</b>) pace</span><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">, the MAPK pathway is a key controller of the chondrocyte differentiation (<b>hypertrophy</b>) pace (Figure 2) (1). FGFR3, working through these pathways, <b>inhibits</b> bone growth.</span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">Figure 2. FGFR3 pathways.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgHra2R_jlQ4TECTLhgprB7_DJSaA0YQj4upAijhyf18IIjn4VEUosLqIY1WjAL5xy0g1tuarCwKdnkjdYg0BOqDhQ4beWJ0TKtzBuvJK5RacNu_wFJXT17q-d5jZ0dcn7zRpflcXZ1tXk/s1600/FGFR3+Signaling+Nature.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="706" data-original-width="926" height="486" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgHra2R_jlQ4TECTLhgprB7_DJSaA0YQj4upAijhyf18IIjn4VEUosLqIY1WjAL5xy0g1tuarCwKdnkjdYg0BOqDhQ4beWJ0TKtzBuvJK5RacNu_wFJXT17q-d5jZ0dcn7zRpflcXZ1tXk/s640/FGFR3+Signaling+Nature.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;">Signaling pathways activated by FGF/FGFR. FGFs induce dimerization,
kinase activation and transphosphorylation of tyrosine residues of
FGFRs, leading to activation of downstream signaling pathways. Multiple
pathways are stimulated by FGF/FGFR signaling such as Ras-MAP kinase,
PI-3 kinase/AKT and PLC-γ pathways. Furthermore, FGF signaling can also
stimulate STAT1/p21 pathway. FGF/FGFR signaling also phosphorylates the
Shc and Src protein. FGF/FGFR play crucial roles in the regulation of
proliferation, differentiation and apoptosis of chondrocytes via
downstream signaling pathways. From </span></span><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;">Su N et al., </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;">Bone Res. 2014 (2). Reproduced here for educational purposes only.</span></span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br />Don't worry about the complexity here, visit the blog's <a href="https://tratando-acondroplasia.blogspot.com/p/glossario-glossary.html">glossary </a>for a brief description of the growth plate and its layers. Other articles of the blog also contain more detailed descriptions of the growth plate (you could try this <a href="https://tratando-acondroplasia.blogspot.com/2019/06/treating-achondroplasia-cnp-in-spotlight.html">one</a>). <br /><br /> <i><b>Statins for achondroplasia?</b></i></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="bi5kl-0-0"><span data-text="true"> </span></span></span></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="bi5kl-0-0"><span data-text="true">Statins have been under the spotlight since 2014, when a Japanese group published an elegant study exploring the use of statins for achondroplasia: they found out that statins were able to rescue bone growth in a model of achondroplasia (you can read more <a href="https://tratando-acondroplasia.blogspot.com.br/2014/12/treating-achondroplasia-with-statins.html">here</a>) (3). However, they could not elucidate how those drugs were working (their mechanism of action). Later on, the Czech group lead by <a href="https://www.achondroplasia-registry.cz/index-en.php">Dr. Pavel Krejci</a> published a study in which they ruled out any direct effect of statins on FGFR3 (4), keeping the question of how statins could have rescued bone growth in that original study without an appropriate answer. </span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="crhai-0-0"><span data-text="true">Thinking about therapeutic solutions for achondroplasia statins could turn to be a handy solution: they are inexpensive, have a known safety profile and have been largely used for several clinical indications, including in children and pregnant women. Read more about statins <a href="https://tratando-acondroplasia.blogspot.com/2018/04/treating-achondroplasia-review-of.html">here</a>.<i><b> </b></i></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="crhai-0-0"><span data-text="true"><i><b>If statins don't block FGFR3, how do they rescue bone growth?</b></i></span></span></span></span></span></div>
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<li><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="crhai-0-0"><span data-text="true">Statins restore chondrocyte proliferation</span></span></span></span></span></li>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">A very recent study published by another Japanese group seems to have finally unveiled the mechanism of action of these drugs, explaining how statins could induce bone growth in achondroplasia.</span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">Ishikawa et al. (5) found out that <i>fluvastatin</i>, one of the statins, was able to increase the expression of one of the key regulators of bone growth, a protein called <i>Indian Hedgehog</i> (IHH). IHH, in turn, induces the release of a </span></span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">local </span></span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">growth plate peptide called <i>Peptide related to Parathyroid Hormone</i> (PTHrP). When PTHrP is released in the growth plate, it stimulates chondrocytes to stay in a proliferative state (1), delaying their transition to the hypertrophic stat</span></span></span></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">e. This <a href="http://tratando-acondroplasia.blogspot.com.br/2012/07/parathyroid-hormone-to-treat.html">article </a>of the blog has more information about the IHH-PTHrP activities in the growth plate.</span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">Therefore, both IHH and PTHrP are bone growth promoters, in contrast with FGFR3, which works naturally as a growth brake in the growth plate. </span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span style="font-size: x-small;"><br /></span></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><i><b>Is there any correlation between FGFR3 and IHH ?</b></i><span data-offset-key="c0fid-0-0"><span data-text="true"> </span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">Back in 2001, Chen et al. (6) demonstrated that FGFR3 had a direct inhibitory effect in the IHH-PTHrP axis in the growth plate (Figure 3). </span></span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true"><span style="font-family: "trebuchet ms" , sans-serif;">The
exact mechanism by which FGFR3 inhibits IHH and PTHrP remains elusive
although it seems that one of the chemical pathways activated through
FGFR3 (the STAT1 pathway - Figure 2) induces cell cycle inhibitors (agents that
block cell multiplication) leading to inhibition of IHH (which is, as
said above, a cell proliferation promoter).</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">Figure 3. Crosstalk between FGFR3 and IHH in the growth plate. </span></span></span></span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi0bPV_c0XsIJ4_CGeqrN6f32RBAfOSfNqnJD_wMbxpXyYPVU1lUiqp3KP7w70kazFxeDz9Zve4toNifm2uFyi7GBAON6xrSNiQZm8iZdZnuhCtL7MAYOd9ZFd0ywUBO3TTJlAYB-GSJIE/s1600/ChenFGFR3_IHH_PTHrP+Crosstalk+2001.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="468" data-original-width="241" height="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi0bPV_c0XsIJ4_CGeqrN6f32RBAfOSfNqnJD_wMbxpXyYPVU1lUiqp3KP7w70kazFxeDz9Zve4toNifm2uFyi7GBAON6xrSNiQZm8iZdZnuhCtL7MAYOd9ZFd0ywUBO3TTJlAYB-GSJIE/s400/ChenFGFR3_IHH_PTHrP+Crosstalk+2001.gif" width="205" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;">Model of the relations between FGF-FGFR3 and IHH-PTHrP–PTHrP-R signaling
in endochondral bone formation. FGF-FGFR3 and IHH-PTHrP–PTHrP-R signals
are transmitted by two integrated parallel pathways that mediate both
overlapping and distinct functions during the growth of long bones. Both
FGFR3 and IHH affect chondrocyte proliferation. However, FGFR3 is a
negative regulator of bone growth, whereas IHH positively regulates bone
growth. Evidence suggests that FGF-FGFR3 signaling induces activation
of STAT proteins, upregulation of the expression of cell cycle
inhibitors and downregulation of IHH expression. Both FGF-FGFR3 and
PTHrP–PTHrP-R signals inhibit chondrocyte differentiation, and both
signals appear to act in a dominant and independent manner. From Chen L et al. Hum Mol Gen 2001;</span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;">10(5):457-65 (6). </span></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;">Reproduced here for educational purposes only.</span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br />So, in summary Ishikawa et al. found out that statins seem to restore the IHH-PTHrP axis in chondrocytes affected by FGFR3 signaling, improving these cells' ability to proliferate.<br /><i><b><br />Why is this finding important?</b></i></span></span></div>
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</span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true"> </span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span data-offset-key="c0fid-0-0"><span data-text="true">As we saw above, FGFR3 inhibits bone growth by reducing both the chondrocyte proliferation rate and its ability to differentiate and enlarge (to become mature, a process called hypertrophy). These two chondrocyte's stages<i><b> </b></i>represent the core of the bone growth process.</span></span></span></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;">To
put this information in context and help readers to understand its
relevance it is important to know that the current most advanced
potential therapy for achondroplasia, vosoritide, which is a <i>C-type
natriuretic peptide</i> (CNP) analogue, works specifically over the MAPK
pathway, so it rescues only one of the key processes regulated by FGFR3 (7).</span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif; font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">In this context,</span> it is possible that strategies that aim to inhibit the activity of FGFR3 directly might provide better outcomes in terms of bone growth rescue because they would be affecting both main pathways triggered by this receptor (Figure 2). This is the case of recifercept (TA-46) and infigratinib (BGJ-398) (check out the articles in the blog reviewing these molecules).</span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br />In conclusion, the data provided by Ishikawa et al. may provide grounds for investigators to explore the combination of therapies targeting the MAPK pathway - all CNP-based therapies, anti-MAPK kinase inhibitors and meclizine - with statins, taking advantage of their unique mechanisms of action. These combinations might work in sinergy to rescue bone growth in achondroplasia and in other skeletal dysplasias in which FGFR3's excessive activity plays a relevant role.<br /><br /><i><b>References</b></i><br /><br />1. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579395/#">Long F, Ornitz DM</a>. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 2013;5(1):a008334. Free access.<br /> <br />2. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472122/"> Su N et al.</a> Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res. 2014;2:14003. Free access.<br /><br /> 3. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al.</a> Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014 ;513(7519):507-11. <br /><br /> 4. <a href="https://www.oarsijournal.com/article/S1063-4584(17)31024-5/fulltext">Fafilek B et al.</a> Statins do not inhibit the FGFR signaling in chondrocytes. Osteoarthritis Cartilage. 2017 Sep;25(9):1522-1530. Free access. <br /><br /> 5. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31327238">Ishikawa M et al</a>. The effects of fluvastatin on indian hedgehog pathway in endochondral ossification. Cartilage. 2019 Jul 22:1947603519862318. <br /><br /> 6. <a href="https://academic.oup.com/hmg/article/10/5/457/2901553">Chen L et al.</a> A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 2001; 10(5):457-65. Free access.<br /><br /> 7. <a href="https://www.cell.com/ajhg/fulltext/S0002-9297(12)00537-X">Lorget F et al.</a> Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012 ;91(6):1108-14. Free access.</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /><br /> <br /><br /><br /> </span></span></div>
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Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-6879859337759828432019-07-02T12:01:00.001-04:002019-07-05T21:34:42.775-04:00Tratando la acondroplasia: el CNP en el centro de la atención<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><i>Traducción: Google Translator, con revisión del Autor.</i> </span></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><i><b>¡Extra, Extra!</b></i><br /><br />Hay tantas noticias recientemente publicadas sobre el <i>péptido natriurético del tipo C</i> (CNP) para la acondroplasia y otros desórdenes óseos que es difícil elegir por dónde empezar.<br /><br /><b><i>Pero, espere un ratito...</i></b><br /><br />Yo sé, lo sé, todo lo que queremos hablar es sobre el CNP. Pero sea paciente, pues creo que un poco de información básica antes puede facilitar la comprensión sobre el CNP, el <i>receptor del factor de crecimiento de fibroblastos 3</i> (FGFR3) y la acondroplasia y cómo poner toda la nueva información en contexto. Entonces, vamos a empezar con una breve revisión de cómo crecen los huesos.<br /><br /><b><i>Cómo los huesos crecen</i></b><br /><br />Como los diecisiete lectores de este blog saben, el crecimiento óseo es un proceso largo, estructurado y muy complejo que ocurre durante el desarrollo de un niño hasta la edad adulta. Influenciado por decenas de agentes locales y sistémicos, el proceso de crecimiento óseo puede ser visto como una sinfonía de Mozart, donde muchos instrumentos diferentes actúan juntos en perfecta armonía para crear un arte maravilloso. Si usted parara para pensar en eso, lo que está en juego y cómo se alcanza, usted concluirá que es un milagro natural. Cada jugador en el proceso de crecimiento trabaja en sintonía fina para alcanzar lo que está planeado en nuestro ADN.<br /><br />Nuestros huesos largos crecen a partir de capas finas de cartílago localizadas en sus extremidades llamadas <i>placas de crecimiento</i>. En las placas de crecimiento, los <i>condrocitos</i>, las células maestras del crecimiento óseo, "despiertan" de un estado latente, inician un frenesí proliferativo, se vuelven muy aumentados y, al final de su ciclo de vida, dan lugar a los <i>osteoblastos</i>, células constructores de hueso (Figura 1) (1). Como se ha dicho anteriormente, este proceso está regulado por muchos agentes locales y sistémicos. Cuando no están en equilibrio, el proceso normal es comprometido, llevando a un crecimiento atrofiado o excesivo.<br /><br />Figura 1. Placa de crecimiento.</span></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjDM525Rqo562bI5NxvU1nyNzD0ysCQpvzVqmjEoCogxz1L9PWFILNJBF1ASrnIF6zIvy0QB4XoMvMp8jF-k4tvcdwKkJ8GEBCnxHNaGw1YgNc_o83B0tavpthNI9Yk2vnrTeyw0ANU3Oc/s1600/GrowthPlate04b.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="385" data-original-width="603" height="408" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjDM525Rqo562bI5NxvU1nyNzD0ysCQpvzVqmjEoCogxz1L9PWFILNJBF1ASrnIF6zIvy0QB4XoMvMp8jF-k4tvcdwKkJ8GEBCnxHNaGw1YgNc_o83B0tavpthNI9Yk2vnrTeyw0ANU3Oc/s640/GrowthPlate04b.jpg" width="640" /></a></span></span></div>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><br /><b><i>¿Qué sucede en la acondroplasia?</i></b><br /><br />En la acondroplasia, el FGFR3, uno de los agentes locales que regulan cómo los condrocitos despiertan, proliferan y crecen, está trabajando demasiado debido a una mutación en su estructura (2,3). Una vez que la acción normal del FGFR3 es la de reducir el ritmo de proliferación e <i>hipertrofia</i> (crecimiento) de los condrocitos, cuando está trabajando excesivamente, los condrocitos simplemente paran sus funciones normales y el crecimiento óseo es severamente comprometido.<br /><br />El FGFR3 es el que se llama una enzima receptora. Se queda atravesado en la membrana celular de los condrocitos, exactamente como una antena en la parte superior del techo de la casa (Figura 2). Mientras que una antena de TV captura señales de TV para entregarlas en nuestros televisores dentro de casa, el FGFR3 transmite mensajes químicos proporcionados por los FGFs fuera de la célula al núcleo de la célula.<br /><br />Básicamente, cuando un FGF se une a la parte del FGFR3 que está fuera de la célula, él activa ("liga") el FGFR3 iniciando una serie de reacciones químicas que consisten en una enzima activando la vecina y ésta la siguiente como en una cadena de dominós, hasta la última, que entra en el núcleo de la célula (Figura 3). Dentro del núcleo de la célula, esta última enzima activará agentes locales que desencadenan (o interrumpen) la producción de proteínas a partir del ADN, cada una de ellas con funciones distintas. En los condrocitos, las señales provenientes del FGFR3 "dicen" al núcleo de la célula para interrumpir las actividades de multiplicación celular. Si los condrocitos dejan de multiplicarse, el crecimiento óseo queda comprometido (2,3).<br /> </span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">Figura 2. El FGFR3 es como una antena en el techo de la casa, captando señales de fuera de la célula y entregándolos al núcleo de la célula.</span></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhF-2ZC3RjjC1of5S5SnnPzlX1vahyv44AjfuB2d-5a0nymXJqvCaRndw4cDkvqqaut09KD2PCfjkmL3IdgIW9Q0S_K5TNFQsZBnyoP00VY4XQgXmWYS6Z9s9r_ugLHpk7qkcIwbSMUXhU/s1600/AntennaFGFR3b.JPG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="612" data-original-width="1600" height="244" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhF-2ZC3RjjC1of5S5SnnPzlX1vahyv44AjfuB2d-5a0nymXJqvCaRndw4cDkvqqaut09KD2PCfjkmL3IdgIW9Q0S_K5TNFQsZBnyoP00VY4XQgXmWYS6Z9s9r_ugLHpk7qkcIwbSMUXhU/s640/AntennaFGFR3b.JPG" width="640" /></a></span></span></div>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">Figura 3. Vías de señalización del FGFR3.</span></span></span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhcj5PHrhtVstIH5c2Ve9_cOGgRsHghFsNBJiQo9av7BGTT5OsNOVavuNhcrNZcC_sXionuHPTiaSZ0Cq-gboL0Fk2a6V4WF3h62OKpES88f8H7KykN5IeIdpgTloRpg4pp7loVvSU3Vcc/s1600/FGFR3+cascade+2b.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="708" data-original-width="929" height="486" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhcj5PHrhtVstIH5c2Ve9_cOGgRsHghFsNBJiQo9av7BGTT5OsNOVavuNhcrNZcC_sXionuHPTiaSZ0Cq-gboL0Fk2a6V4WF3h62OKpES88f8H7KykN5IeIdpgTloRpg4pp7loVvSU3Vcc/s640/FGFR3+cascade+2b.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">De<a href="https://www.nature.com/articles/boneres20143"> Su N et al</a>. Bone Res 2014; 2: 14003. Reproducido aquí sólo con fines educativos.</span></span></span></span></td></tr>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><br />Como se puede ver en la Figura 3, la activación del FGFR3 acciona varias cascadas enzimáticas (las vías señaladoras). La cascada MAPK (para Proteína Quinasa Activada por Mitógeno) es la más importante para nosotros en el contexto del CNP. La cascada MAPK consiste en las enzimas RAS, RAF, MEK y ERK (a la derecha en la Figura 3) (3). La enzima ERK es la que alcanza el núcleo de la célula.<br /><br />Varios estudios han establecido que, bajo la activación del FGFR3, la MAPK es especialmente responsable de regular el aumento de los condrocitos (hipertrofia, ver Figura 1) (2,3). La zona hipertrófica parece ser la capa más importante en la placa de crecimiento en relación al crecimiento óseo. Bajo la superativación del FGFR3 en la acondroplasia, hay menos condrocitos proliferando y aumentando y aquí es donde el CNP tiene un importante papel. Vamos a ver cómo funciona.<br /><i><b><br />CNP y FGFR3</b></i><br /><br />El CNP se produce dentro de la placa de crecimiento y funciona como un promotor de crecimiento óseo, luego tiene un efecto opuesto al FGFR3. Cuando se libera, este pequeño péptido se une a su receptor en la membrana celular de los condrocitos (de la misma forma que el FGF se une al FGFR3) y activa una vía química dentro de los condrocitos que inhibe la MAPK a nivel de la enzima RAF (Figura 4) (2). ¿Puedes ver el punto? El CNP trabaja naturalmente reduciendo la actividad de la vía FGFR3.<br /><br />Figura 4. Interacción de las vías del FGFR3 y CNP.</span></span></span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEihoGk1mTOIdLkUXGaLYEdKKtXYOH8Mj14k_5PEaY9T2F83RXo4JaejyPPIYlhayEqJh2tPkfbMrzfrqoJ9g4sP60bKuUDmpNSinuZLad5J6JNRqMIQ4wCIlIzzPAIdH_zOUx41Fl9IK-Q/s1600/william-horton+FGFR3_CNP+crosstalkb.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="412" data-original-width="560" height="470" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEihoGk1mTOIdLkUXGaLYEdKKtXYOH8Mj14k_5PEaY9T2F83RXo4JaejyPPIYlhayEqJh2tPkfbMrzfrqoJ9g4sP60bKuUDmpNSinuZLad5J6JNRqMIQ4wCIlIzzPAIdH_zOUx41Fl9IK-Q/s640/william-horton+FGFR3_CNP+crosstalkb.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">De<a href="https://academic.oup.com/hmg/article-pdf/25/R1/R2/7145150/ddv419.pdf"> Klag KA y Horton WA</a>. Hum Mol Gen 2016; 25: R2-R8. Reproducido aquí sólo con fines educativos.</span></span></span></span></td></tr>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><i><b><br />CNP y crecimiento óseo</b></i><br /><br />Las mutaciones de pérdida de función en el gen del CNP o en el receptor del CNP (llamado NPRB), que perjudican su función normal, causan una displasia ósea genética muy rara llamada <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=acromesomelic+dysplasia+maroteaux+type"><i>displasia acromesomélica del tipo Maroteaux</i></a>, que tiene algunas características que se asemejan a la acondroplasia (4) 5). Por el contrario, las mutaciones que llevan a la ganancia en función del CNP o su receptor conducen al crecimiento excesivo de los huesos (6,7). El papel del CNP en el crecimiento óseo fue descrito también en modelos de ratones con acondroplasia y de ausencia de CNP (8).<br /><br /><i><b>Haciendo del CNP una terapia viable para la acondroplasia</b></i><br /><br />La vida no es fácil para los péptidos. Los procesos de la placa de crecimiento están rígidamente regulados, como ya hemos visto, pero en realidad esto ocurre en todos los procesos orgánicos en funcionamiento en nuestro cuerpo. Proteínas y péptidos activos circulantes como el CNP pueden iniciar, aumentar, disminuir o interrumpir muchas reacciones químicas, de modo que el organismo posee varios sistemas para eliminar estos agentes de la circulación, para evitar que causen efectos indeseables. Uno de estos sistemas está compuesto por enzimas en la sangre que tienen como objetivo péptidos como el CNP (se llaman endopeptidasas o endoproteasas). Esto es tan cierto que, una vez liberado en el torrente sanguíneo, el CNP durará sólo dos minutos (lo que se llama la vida media, <i>half-life</i>) (9).</span></span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><br /></span></span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><span class="" title="">Hace unos diez años, l</span></span>os científicos probaron que el CNP tiene un papel positivo en el crecimiento óseo y que podría contrarrestar el efecto inhibitorio del FGFR3 en la acondroplasia (8), pero con esa corta vida media de apenas 2 min, como ellos podrían administrar el CNP para restaurar el crecimiento hueso? </span></span><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><span class="" title="">Ellos fueron capaces de demostrar que</span></span> la infusión continua de CNP tuvo un efecto positivo en el crecimiento óseo (8), pero tener una bomba de infusión conectada al cuerpo para lograr el efecto no parecía ser una opción razonable cuando se pensaba en terapias a largo plazo en aquel tiempo.<br /><br />Por lo tanto, era necesario encontrar otras soluciones. El CNP forma parte de una familia de tres moléculas estrechamente relacionadas, denominadas <i>péptidos natriuréticos</i>. Uno de ellos, el <i>péptido natriurético del cerebro</i> (BNP) mostró ser naturalmente más resistente a las endoproteasas debido a una "cola" prolongada que el CNP no posee (Figura 5). Con ese conocimiento en manos, los investigadores desarrollaron una forma de CNP que posee una cola prolongada similar al BNP (10).</span></span></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><br /><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">Figura 5. Péptidos Natriuréticos.</span></span></span></span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi8SWBOE0iKAR8TwnDP_aEOpwHAYQNdecBiFXlpZoxMjpzHrwaL0P2rW_3eXyisRGjJ6QKYs15l8KZEafhtbK3Ys9Z2S-Zew62D6h6bogc1O_ApWid6IqGLoHZkCGp2vlqGjorhGiRElMU/s1600/NatriureticPeptides2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="257" data-original-width="1280" height="128" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi8SWBOE0iKAR8TwnDP_aEOpwHAYQNdecBiFXlpZoxMjpzHrwaL0P2rW_3eXyisRGjJ6QKYs15l8KZEafhtbK3Ys9Z2S-Zew62D6h6bogc1O_ApWid6IqGLoHZkCGp2vlqGjorhGiRElMU/s640/NatriureticPeptides2.jpg" width="640" /></a></div>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><br /><i><b>Desarrollando el vosoritide</b></i><br /><br />El CNP modificado (llamado análogo), que conocemos con el nombre de vosoritide (BMN-111), no sólo retiene las funciones biológicas del péptido original, pero también es más resistente a la neutralización por las enzimas neutralizadoras, con una vida media prolongada 20 minutos. Ser capaz de circular por más tiempo en la corriente sanguínea dio tiempo suficiente para que el vosoritide pudiera alcanzar las placas de crecimiento para ejercer su función esperada (10).<br /><br />De hecho, ambos estudios preclínicos en ratas y monos resultaron en un crecimiento adicional y los resultados recientemente publicados del estudio de fase 2 en niños con acondroplasia demostraron que una inyección subcutánea (SC) una vez al día de voracidad resultó en aumento de la velocidad de crecimiento del hueso y el crecimiento adicional en comparación con lo que se esperaba sin el tratamiento </span></span><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">(10-12)</span></span>. El vosoritide está siendo probado en más de 100 niños en un estudio de fase 3 (<a href="https://www.clinicaltrials.gov/ct2/show/NCT03197766?term=NCT03197766&rank=1">NCT03197766</a>), con resultados que estarán disponibles a finales de este año y si tiene éxito, el medicamento puede estar en el mercado próximo año.<br /><br />Ahora, vamos a echar un vistazo a los resultados del estudio de la fase 2, publicado en el New England Journal of Medicine (NEJM) recientemente (12). En realidad, los principales resultados reportados en este documento ya habían sido divulgados durante el evento "Día de la Investigación y Desarrollo" (R&D Day) realizado por Biomarin en junio de 2018 y repetidos durante la conferencia de JP Morgan en enero pasado. Desafortunadamente, los enlaces a estas presentaciones ya no están disponibles en el sitio web de Biomarin, pero usted puede ver una de las diapositivas de la presentación de R & D Day de junio de 2018 en la Figura 6.<br /><br />Figura 6. Efecto del vosoritide en la velocidad media de crecimiento después de 42 meses en la tercera cohorte del estudio de fase 2 (15mcg/kg).</span></span></span></span><br />
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<span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">Imagen de la presentación del R & D Day de Biomarin (Jun 2018).</span></span></span></span></span></span></div>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">El contenido del estudio de fase 2 está protegido por derechos de autor, así que no puedo reproducir figuras publicadas en la revista, pero el NEJM ha divulgado una imagen en su <a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1">cuenta en Twitter</a> mostrando uno de los principales resultados del estudio (Figura 7).<br /><br />Figura 7. Aumento de la velocidad de crecimiento óseo después de seis meses de inicio del tratamiento con vosoritide.</span></span></span></span><br />
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<a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1813446">Savararayan R et al.</a> NEJM 2019; (correspondiente a la Figura 1A en el
artículo original) obtenida de la <a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1">cuenta Twitter de acceso abierto del NEJM</a> y reproducida aquí sólo con fines educativos.</span></span></span></span></td></tr>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"> </span></span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es">En resumen, el vosoritide (15mcg/kg) fue capaz de restaurar la velocidad de crecimiento óseo en niños con acondroplasia tratadas a un nivel más cercano a la velocidad media de crecimiento óseo observada en niños no afectados (Figura 6). El efecto se mantuvo después de 42 meses de exposición. No puedo mostrar aquí, pero en una de las figuras (Figura 1B en el texto original) se puede interpretar que hay una leve tendencia a una reducción en el efecto sobre el crecimiento óseo a lo largo de los 42 meses (12).<br /><br />De todos modos, el estudio mostró una mejora progresiva en la <i>score-z </i>para altura con 15mcg/kg/día, lo que, en lenguaje del mundo real, significa que la diferencia entre el patrón de crecimiento de los niños expuestos en relación a las curvas de crecimiento estándar disminuyó a lo largo del tiempo (12).<br /><br />Una cuestión que se planteó al inicio del desarrollo clínico de los últimos años fue si la droga causaría el agravamiento de la desproporción del cuerpo. Los resultados de este estudio muestran que esto no ocurrió pero, por otro lado, no hubo mejoría significativa en ese aspecto de la displasia (12). Es necesario recordar que la mayor parte de la desproporción se establece en los dos primeros años de vida, y que los niños en este estudio tenían al menos seis años de edad en el momento de la inscripción, posiblemente demasiado tarde para ver los efectos relevantes en este aspecto de la acondroplasia.<br /><br />En cuanto a la seguridad, parece que el vosoritide tiene un perfil de seguridad razonable, con la mayoría de los eventos adversos relacionados con las reacciones en el lugar de la inyección, que fueron en su mayoría de intensidad leve. La exposición a sustancias biológicas puede desencadenar una respuesta inmunológica del organismo, que puede producir anticuerpos contra la droga administrada. Esto es común en el tratamiento con anticuerpos monoclonales contra el cáncer y otras condiciones inflamatorias, por lo que no es sorprendente que los anticuerpos anti-drogas (ADA) se hayan encontrado en este estudio (12). Sin embargo, parece que la presencia de ADA no afectaría a la eficacia del medicamento (13).<br /><br />¿Cuál será la respuesta a la siguiente pregunta? Una vez que los resultados de los 42 meses de exposición ya estaban disponibles hace un año, ¿por qué resultados más allá de ese punto de corte no fueron incluidos en este estudio, que acaba de ser publicado?</span></span></span></span><br />
<br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><i><b>¿Hay algo que mejorar?</b></i></span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><i><b> </b></i><br />Bien, el vosoritide ha mostrado consistentemente resultados que, si se confirman en el estudio </span><span class="tlid-translation translation" lang="es">de fase 3</span><span class="tlid-translation translation" lang="es"> en curso (<a href="https://www.clinicaltrials.gov/ct2/show/NCT03197766?term=NCT03197766&rank=1">NCT03197766</a>), pueden abrir el camino para ser aprobado para el tratamiento de la acondroplasia el próximo año. Esta es una noticia maravillosa, ya que esta terapia puede ayudar a mejorar la calidad de vida de muchos niños en el futuro. Sin embargo, parece que hay espacio para efectos de crecimiento óseo aún mejores con el CNP.<br /><br />La <a href="https://ascendispharma.com/product-pipeline/transcon-cnp/">Ascendis Pharma</a> está desarrollando otro análogo del CNP (ellos llaman CNP-38, una molécula de CNP con 38 aminoácidos), pero usando tecnología propietaria para mejorar cuanto tiempo su CNP circula para ejercer sus efectos en los huesos. Ellos crearon un sistema de transporte (podemos llamar "taxi") para moléculas delicadas como el CNP (Figura 8). Protegido por el taxi de Ascendis, el TransCon, su CNP mostró tener una vida media mucho más larga en comparación con el vosortide. De hecho, ellos acabaron de publicar los resultados completos de sus estudios preclínicos hechos con el TransCon CNP, que incluyeron pruebas comparando su CNP con el vosoritide (14). En su estudio reprodujeron la molécula correspondiente a el vosoritide, que es un CNP con 39 aminoácidos (o, CNP-39) para comparar con su CNP-38. Vamos a echar un vistazo a este estudio.<br /><br />Figura 8. Sistema de transporte TransCon.</span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"></span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"></span></span></span>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiRiruwDgottafvCPf8iGalVdCo6X_n2cTC4ioEPuD0JiJ98GmfaCFlDDGDPuuGcPDRY51jau5tq3DmY_Wxq6KIxDAxmTbpzcUQBDIE-cz-njDuOfYCC0NH75t8jRij4A_S_cUhJMGRj9U/s1600/updated-transcon2.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="342" data-original-width="994" height="220" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiRiruwDgottafvCPf8iGalVdCo6X_n2cTC4ioEPuD0JiJ98GmfaCFlDDGDPuuGcPDRY51jau5tq3DmY_Wxq6KIxDAxmTbpzcUQBDIE-cz-njDuOfYCC0NH75t8jRij4A_S_cUhJMGRj9U/s640/updated-transcon2.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">De la Ascendis Pharma. Usted puede ver más <a href="https://ascendispharma.com/platform/transcon-technology/">aquí</a>.</span></span></span></td></tr>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><br />En resumen, debido a las características de su taxi y su estructura de CNP, verificaron que su sistema TransCon ofrecía una exposición estable de su CNP por una semana, sin el pico de dosificación en el plasma observado con el vosoritide, por lo tanto, con un mínimo efecto sobre la presión arterial. El efecto en el crecimiento óseo fue al menos tan bueno como con el CNP-39 (Figura 9) (14).<br /><br />Figura 9. Efecto del TransCon CNP (40 y 100 mcg/kg) vs. placebo y CNP-39 en la longitud del cuerpo y los huesos.</span></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"> <table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglz5lm9iU748a4hLMF_zXD7xgMhUZnZ2gFFcOr7GCNGvRUIUJfn9hKTWxXGu-slgIfwR-UhZ-8tmWj13F0oMtBgla-Qye_r5FlESyqE8Gcz2vPa6drJCS0UzqyDcuJL2lLYI6NReI3EhI/s1600/BernholtAscendisTransConCNPEffectBones2019.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="593" data-original-width="820" height="462" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglz5lm9iU748a4hLMF_zXD7xgMhUZnZ2gFFcOr7GCNGvRUIUJfn9hKTWxXGu-slgIfwR-UhZ-8tmWj13F0oMtBgla-Qye_r5FlESyqE8Gcz2vPa6drJCS0UzqyDcuJL2lLYI6NReI3EhI/s640/BernholtAscendisTransConCNPEffectBones2019.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">De
<a href="http://jpet.aspetjournals.org/content/early/2019/06/24/jpet.119.258251"> Breinholt VA et al.</a> J Pharmacol Exp Ther 24 de junio de 2019,
jpet.119.258251. (Artículo de acceso libre). Reproducido aquí sólo con
fines educativos. Pos. Ctrl. = CNP-39.</span></span></span></td></tr>
</tbody></table>
</span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">Ascendis ya realizó un <a href="https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375353&isReview=true">estudio de fase 1</a> con el TransCon CNP en voluntarios sanos y confirmó la larga vida media de su análogo, lo que permitirá una dosis semanal, en contraste con la dosis diaria de voritide. No hubo problemas con la seguridad cardiaca. Ascendis debe iniciar su estudio de fase 2 en niños en breve.<br /><b><i><br />¿Este es el final de la historia?</i></b><br /><br />No, de ninguna manera. La Daiichi Sankio, una industria farmacéutica japonesa, está desarrollando el ASB20123, un nuevo análogo del CNP. En este caso, el compuesto es una molécula de fusión donde la parte activa del CNP se combina con un fragmento de la hormona <i>grelina</i>, otro péptido (Figura 10). Esta ingeniería hace que el CNP sea resistente a la endopeptidasas dando más tiempo para que ejerza sus funciones (15,16). Básicamente, es el mismo principio utilizado para los análogos de Biomarin y de Ascendis.<br /><br />Figura 10. Estructura del ASB20123, un nuevo análogo del CNP.</span></span></span><br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhCH07YgxxNQ6-KCGunLF375rP0tTALiZqaq0MvxBmRXpf9cIvv8zToPgImtDeR1iiuJvolWAdwviAiiUdK_vAP6Y2cr6VNW87CQemgMTnOSdYxSKbpdCnbWzJUnzxKpLc6x-e3NN0CYxc/s1600/ASB20123.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="731" data-original-width="1600" height="292" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhCH07YgxxNQ6-KCGunLF375rP0tTALiZqaq0MvxBmRXpf9cIvv8zToPgImtDeR1iiuJvolWAdwviAiiUdK_vAP6Y2cr6VNW87CQemgMTnOSdYxSKbpdCnbWzJUnzxKpLc6x-e3NN0CYxc/s640/ASB20123.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">De <a href="https://doi.org/10.1371/journal.pone.0212680">Morozumi N et al</a>. PlosOne 2019 (acceso libre), reproducido aquí sólo con fines educativos.</span></span></span></td></tr>
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><br />El ASB20123 demostró efectos positivos claros en el crecimiento óseo, como se ve en sus experimentos en un modelo de rata (Figura 11). Observe que es posible que, bajo la mayor dosis probada, pueda haber ocurrido un crecimiento excesivo. Desafortunadamente, no hay radiografías en este estudio que permitan verificar densidades o formas óseas, pero, de hecho, los investigadores mencionan que el supercrescimiento probablemente ocurrió cuando los animales recibieron dosis más altas (16).<br /><br />Figura 11. Efectos del ASB20123 en el crecimiento en un modelo de ratón.</span></span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjr0CA0AGY-0cQqy9qZfP0uuoxXn6a3L11sFzeJfK_Hx-Drc66V6Fle2UXf8FqOVGjEhmSrDV3zAhMMtcTddRcoLlzKXHnlTPVZtjDQ0EonFPvE6WQVnsTs6on6rTtAHBUecFmULaHUGTU/s1600/ASB20123growtheffects.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="1039" data-original-width="1440" height="460" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjr0CA0AGY-0cQqy9qZfP0uuoxXn6a3L11sFzeJfK_Hx-Drc66V6Fle2UXf8FqOVGjEhmSrDV3zAhMMtcTddRcoLlzKXHnlTPVZtjDQ0EonFPvE6WQVnsTs6on6rTtAHBUecFmULaHUGTU/s640/ASB20123growtheffects.jpg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"></span></span></span><br />
<div style="text-align: justify;">
<span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">Curvas
de crecimiento de ratones ICR juveniles tratados con ASB20123 sc
durante las 8 semanas del período de dosificación y las 4 semanas del
período de lavado. Los datos del peso corporal (A), longitud del cuerpo
(B) y longitud de la cola (C) se muestran en los paneles superiores, y
las fotografías en el panel inferior representan la apariencia grosera
de las ratas en el día 56 (D). Cada valor representa la media ± DP de 10
(para el período de dosificación) o 5 ratas (para el período de
lavado). NS: no significativo (p> 0,05), *: diferencia significativa
(p <0,05) en relación al grupo control por la prueba de Dunnett. De
<a href="https://doi.org/10.1371/journal.pone.0212680">Morozumi N et al.</a> PlosOne 2019 (acceso libre), reproducido aquí sólo con
fines educativos.</span></span></span></div>
</td></tr>
</tbody></table>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es">Los investigadores también probaron el ASB20123 a través de una bomba SC, de nuevo proporcionando una liberación sostenida de su análogo, con mejores resultados de crecimiento. El argumento es que el uso de una bomba SC puede permitir concentraciones estables pero menores de su análogo para promover el crecimiento óseo sin eventos adversos cardíacos (especialmente hipotensión) (16). Bombas SC más nuevas parecen ser más cómodas que los modelos más antiguos y ahorrar a los niños de las inyecciones diarias o semanales. No me siento exactamente cómodo con este enfoque, pero creo que es demasiado pronto para sacar conclusiones al respecto.</span></span></span><br />
<br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"><i><b>Horizonte brillante</b></i><br /><br />El campo de la terapia para la acondroplasia se está llenando. Ahora, hay dos análogos de CNP en desarrollo clínico, uno de ellos, vosoritide, más cerca de la aprobación para el mercado, aguardando resultados de su estudio de fase 3 a finales de este año. El otro, TransCon CNP, sigue para el estudio de fase 2. Therachon está desarrollando el TA-46, una molécula basada en el FGFR3 y proyectada para competir por los FGFs con el receptor mutante (17). Un grupo japonés viene trabajando con la <i>meclizina</i>, un antiguo medicamento antiemético que mostró efectos positivos en el crecimiento óseo (18). <a href="https://www.qedtx.com/achondroplasia/">QED Therapeutics</a>, una pequeña empresa de biotecnología, comenzó a trabajar con <i>infigratinib</i>, una molécula diseñada para bloquear la activación del FGFR (19). El grupo japonés de la Daiichi Sankio acaba de presentar su análogo del CNP (16). La <i>osteocrina</i>, un péptido natural, mostró mejorar el crecimiento óseo bloqueando el NPRC (un receptor regulador para péptidos natriuréticos), dando más tiempo para el CNP ejercer sus efectos en el crecimiento óseo (20). Los investigadores descubrieron que una familia de drogas usadas para bajar el colesterol, las <i>estatinas</i>, también puede ser usada para mejorar el crecimiento óseo en la acondroplasia (21). Además, ya existen investigaciones iniciales explorando edición genética para tratar la acondroplasia (a ser revisada en un artículo futuro).<br /><br /><i><b>Sin embargo, esto todavía no es el fin</b></i><br /><br />Con el conocimiento creciente sobre las vias químicas alteradas en la acondroplasia y las investigaciones para ponerlas en equilibrio nuevamente, los investigadores también comenzaron a explorar el uso de terapias inicialmente proyectadas para la acondroplasia en otras displasias esqueléticas donde las vías del FGFR pueden tener un papel relevante. El ejemplo más natural es la hipocondroplasia, que también es causada por mutaciones en el FGFR3. Pero hay otras iniciativas.<br /><br />Por ejemplo, un estudio mostró que el BMN111 (vosoritide) tuvo efectos positivos en un modelo del síndrome de Crouzon, una craneosinostosis asociada a una mutación del FGFR2 (22). La vía de la MAPK, clave en la acondroplasia, también es fundamental en la familia de desórdenes genéticos denominados RASopatías, en las cuales enzimas de la vía MAPK o sus reguladores tienen mutaciones que perjudican sus funciones normales, lo que causa una infinidad de complicaciones clínicas. Las RASopatías incluyen la Neurofibromatosis y el Síndrome de Noonan, entre varios otros trastornos. Un trabajo reciente con estatinas en el Síndrome de Noonan mostró que ellas fueron capaces de rescatar el crecimiento en esa RASopatía (23). El mismo grupo que trabaja con el ASB20123 probó el CNP en un modelo de ratón con síndrome cardio-facial-cutáneo, otra RASopatía, con resultados positivos (24).<br /><br />Hay novedades aún mejores. Algunos meses atrás, investigadores chinos publicaron un estudio en el que descubrieron que el FGFR3 tiene un papel importante en el mecanismo de disturbios genéticos ligados a las mutaciones en el gen SLC26A2, que incluyen la <i>displasia díastrófica</i>. Se mostró que inhibir el FGFR3 con el infigratinib (el bloqueador del FGFR en desarrollo por la QED) mejoró la formación ósea y los fenotipos de dos formas letales de disturbios del SLC26A2: <i>acondrogénesis tipo IB</i> y <i>atelosteogénesis tipo II</i> (25). Si ellos lograron mejorar los fenotipos en aquellas formas devastadoras de desórdenes genéticos ligados al transporte de sulfato, ¿cuáles serían los resultados en formas más leves, como la displasia díastrófica?<br /><br />La gran cuestión ya no es si existe, o habrá, cualquier tratamiento disponible. La cuestión ahora es: ¿en qué otras displasias esqueléticas terapias para la acondroplasia también pueden ofrecer beneficios?<br /><br /><i><b>División</b></i><br /><br />La comunidad interesada se ha dividido últimamente con opiniones divergentes sobre cuáles son realmente los propósitos de estas nuevas terapias potenciales. Algunos afirman que serían sólo para efectos cosméticos, y una amenaza a la diversidad humana. Un torrente de acusaciones y un juicio severo sobre los padres tomar decisiones sobre sus hijos sin su consentimiento se ha publicado en los medios sociales, como si las decisiones no son lo que los padres siempre toman todos los días de las más banales a las más complejas cuestiones posible en relación con sus hijos.</span></span></span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="es"><i><b>Abrazando el cambio</b></i><br /><br />No hace mucho tiempo, no había nada que hacer después del diagnóstico de un desorden genético, pero resignarse, pues no había perspectivas al frente.<br /><br />Ahora, el tiempo para la resignación ha terminado. Las terapias para desórdenes genéticos del crecimiento óseo están en camino y no tienen nada que ver con la reducción de la diversidad humana, como algunos han declarado últimamente. Ellas tienen que ver con proporcionar una vida mejor para los niños afectados, futuros adultos.<br /><br />Al restaurar el crecimiento óseo, muchas complicaciones clínicas observadas en displasias óseas podrán finalmente prevenirse o minimizarse. Esto resultará en un mejor funcionamiento y una mejor calidad de vida para nuestros amados hijos, a medida que crecen y se vuelven adultos. Usted puede imaginar que su hijo no tiene que pasar por grandes cirugías todavía bebé, o tener que lidiar con complicaciones ortopédicas y neurológicas a lo largo de la vida? (26, 27) ¿Eso no sería lo suficientemente bueno?<br /><br />Y finalmente, si restaurar el crecimiento óseo en la acondroplasia y otros desórdenes óseos, hará los individuos tratados más altos, mejor aún, pues ellos serán capaces de enfrentar mejor los muchos desafíos existentes en el mundo allá afuera. Si usted todavía no está allí, debe comenzar a pensar en abrazar el cambio pronto. El está llegando.<br /><br /><i><b>Referencias</b></i></span></span></span><span class="tlid-translation-gender-indicator translation-gender-indicator"></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 1. <a href="https://www.ncbi.nlm.nih.gov/pubmed/12748651">Kronenberg HM</a>. Developmental regulation of the growth plate. Nature 2003;423 (6937):332–6.<br /> <br /> 2. <a href="https://academic.oup.com/hmg/article-pdf/25/R1/R2/7145150/ddv419.pdf">Klag KA and Horton WA.</a> Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Gen 2016; 25:R2-R8.<i> Free access</i>.<br /> <br /> 3. <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/dvdy.24479">Ornitz DM, Legeai-Mallet L</a>. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 2017; 246(4):291–309. Free access.<br /> <br /> 4. <a href="https://www.nature.com/articles/gim201766.pdf">Hisado-Oliva A et al</a>. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature.Genet Med 2018;20(1):91-7. <i>Free access</i>. <br /> <br /> 5. <a href="https://academic.oup.com/jcem/article-pdf/99/4/E713/9050688/jcemE713.pdf">Amano N et al.</a> Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. J Clin Endocrinol Metab 2014 Apr;99(4):E713-8. <i>Free access</i>. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 6. <a href="https://www.ncbi.nlm.nih.gov/pubmed/24259409">Miura K</a> et al. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A 2014;164A(1):156-63. <br /> <br /> 7. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25728306">Ko JM</a> et al. Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1). Am J Med Genet A 2015; 167A(5):1033-8. <br /> <br /> 8. <a href="https://www.jstage.jst.go.jp/article/endocrj/57/8/57_K10E-164/_pdf/-char/en">Yasoda A, Nakao K.</a>. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocr J 2010;57(8):659-66. <i>Free access</i>.<br /> <br />9.<a href="https://www.ncbi.nlm.nih.gov/pubmed/8200946"> Hunt PJ et al</a>. Bioactivity and metabolism of C-type natriuretic peptide in normal man. J Clin Endocrinol Metab 1994; 78: 1428-35. <br /> <br /> 10. <a href="https://www.cell.com/action/showPdf?pii=S0002-9297%2812%2900537-X">Lorget F et al</a>. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 2012; 91(6):1108–14. <i>Free access</i>.<br /> <br /> 11. <a href="http://jpet.aspetjournals.org/content/jpet/353/1/132.full.pdf">Wendt DJ et al</a>. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 2015;353:132–49. <i>Free access</i>.<br /> <br /> 12. <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1813446">Savarirayan R et al</a>. C-type natriuretic peptide analogue therapy in children with achondroplasia. NEJM June 18, 2019. DOI: 10.1056/NEJMoa1813446. Published ahead of print.<br /> <br /> 13. <a href="https://isds2019.exordo.com/programme/presentation/283">Chan D et al.</a> Pharmacokinetic and exposure-response analysis of vosoritide in children with achondroplasia. Abstract. To be presented at the ISDS 2019 Meeting, Oslo, Norway, Sep 12, 2019. <i>Free access</i>.<br /><br />14.<a href="http://jpet.aspetjournals.org/content/jpet/early/2019/06/24/jpet.119.258251.full.pdf"> Breinholt VA et al.</a> TransCon CNP, a sustained-release C-Type Natriuretic Peptide prodrug, a potentially safe and efficacious new therapeutic modality for the treatment of comorbidities associated with FGFR3-related skeletal dysplasias. J Pharmacol Exp Ther June 24, 2019, jpet.119.258251. Published ahead of print.<i> Free access</i>.<br /> <br /> 15. <a href="https://www.ncbi.nlm.nih.gov/pubmed/28899838">Morozumi N et al</a>. Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties. Peptides 2017;97:16-21. <br /><i>Free access</i>.<br /> <br /> 16.<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680#pone-0212680-g007"> </a><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680#pone-0212680-g007">Morozumi N et al</a>. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoS One 2019 Feb 22;14(2):e0212680. <i>Free access</i>. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 17. <a href="https://stm.sciencemag.org/content/5/203/203ra124/tab-pdf">Garcia S et al</a>. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 2013 Sep 18;5(203):203ra124. <i>Free access</i>.<br /> <br />18. <a href="https://www.nature.com/articles/s41598-017-07044-8.pdf">Matsushita M</a>. Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia. Sci Rep 2017;7(1):7371. <i>Free access</i>.<br /> <br /> 19. <a href="https://www.jci.org/articles/view/83926/pdf">Komla-Ebri D et al</a>. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016;126(5):1871-84. <i>Free access</i>. <br /> <br /> 20. <a href="https://www.jci.org/articles/view/94912/pdf">Kanai Y et al</a>. Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance. J Clin Invest 2017;127(11):4136-47. <i>Free access</i>. <br /> <br /> 21. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al</a>. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014; 513(7519):507-11. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 22. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201492">Holmes G et al</a>. C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=natriuretic+peptdie+crouzon+syndrome#">PLoS One.</a> 2018;13(7):e0201492. <i>Free access</i>.<br /> <br /> 23.<a href="https://academic.oup.com/hmg/article-pdf/27/13/2276/25061148/ddy133.pdf">Tajan M et al</a>. Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth. Hum Mol Genet 2018;27(13):2276-89. <i>Free access</i>.<br /> <br /> 24. <a href="https://www.ncbi.nlm.nih.gov/pubmed/30239744">Inoue SI et al</a>. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome. Hum Mol Genet 2019; 28(1):74-83. <br /> <br /> 25. <a href="https://www.ebiomedicine.com/article/S2352-3964(19)30010-6/pdf">Zheng C et al</a>. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 2019;40:695-709. <i>Free access</i>.<br /> <br /> 26. <a href="https://www.ncbi.nlm.nih.gov/books/NBK1152/">Pauli RM, Legare JM</a>. Achondroplasia. 2018. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. <i>Free access</i>.<br /> <br /> 27. <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.13542">Fredwall SO et al</a>. Current knowledge of medical complications in adults with achondroplasia: A scoping review. Clin Genet. 2019 Mar 27. <i>Free access</i>.<br /><br /> <br /><br /> </span></span><br />
<span class="tlid-translation translation" lang="es"><span class="tlid-translation translation" lang="es"></span></span><br />Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-21787340437650264072019-06-30T11:37:00.001-04:002019-07-05T21:31:27.760-04:00Tratando a acondroplasia: o CNP no centro das atenções<div class="text-wrap tlid-copy-target">
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><i><b>Extra, Extra!</b></i><br /><br />Há tantas notícias recentemente publicadas sobre o <i>peptídeo natriurético do tipo C</i> (CNP) para a acondroplasia e outras desordens ósseas que está difícil escolher por onde começar.<br /><br /><b><i>Mas, espere um minuto...</i></b><br /><br />Eu sei, eu sei, tudo o que queremos falar é sobre o CNP. Mas seja paciente, pois creio que um pouco de informação básica antes pode facilitar a compreensão sobre o CNP, o <i>receptor do fator de crescimento de fibroblastos 3</i> (FGFR3) e a acondroplasia e como botar todas as novas informações em contexto. Então, vamos começar com uma breve revisão de como os ossos crescem.<br /><br /><i><b>Como os ossos crescem</b></i><br /><br />Como os dezessete leitores deste blog sabem, o crescimento ósseo é um processo longo, estruturado e muito complexo que ocorre durante o desenvolvimento de uma criança até a idade adulta. Influenciado por dezenas de agentes locais e sistêmicos, o processo de crescimento ósseo pode ser visto como uma sinfonia de Mozart, onde muitos instrumentos diferentes atuam juntos em perfeita harmonia para criar uma arte maravilhosa. Se você parasse para pensar sobre isso, o que está em jogo e como ele é alcançado, você concluiria que é um milagre natural. Cada jogador no processo de crescimento trabalha em sintonia fina para alcançar o que está planejado em nosso DNA.<br /><br />Nossos ossos longos crescem a partir de camadas finas de cartilagem localizadas em suas extremidades chamadas <i>placas de crescimento</i>. Dentro das placas de crescimento, os <i>condrócitos</i>, as células mestras do crescimento ósseo, "despertam" de um estado dormente, iniciam um frenesi proliferativo, tornam-se muito aumentados e, no final de seu ciclo de vida, dão lugar aos <i>osteoblastos</i>, </span><span class="tlid-translation translation" lang="pt">células construtoras d</span><span class="tlid-translation translation" lang="pt">os ossos (Figura 1) (1). Como dito acima, este processo é regulado por muitos agentes locais e sistêmicos. Quando eles não estão em equilíbrio, o processo normal é comprometido, levando a um crescimento atrofiado ou excessivo.<br /><br />Figura 1. Placa de crescimento.</span></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><br /><br /><i><b>O que acontece na acondroplasia?</b></i><br /><br />Na acondroplasia, o FGFR3, um dos agentes locais que regulam como os condrócitos despertam, proliferam e crescem, está trabalhando demais devido a uma mutação em sua estrutura (2,3). Uma vez que a ação normal do FGFR3 é a de reduzir o ritmo de proliferação e hipertrofia </span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">(crescimento)</span> dos condrócitos, quando está trabalhando excessivamente, os condrócitos simplesmente param suas funções normais e o crescimento ósseo é severamente comprometido.<br /><br />O FGFR3 é o que é chamado de uma enzima receptora. Ele fica atravessado na membrana celular dos condrócitos, exatamente como uma antena no topo do telhado da casa (Figura 2). Enquanto uma antena de TV captura sinais de TV para entregá-los em nossas TVs dentro de casa, o FGFR3 transmite mensagens químicas fornecidas pelos FGFs de fora da célula para o núcleo da célula.<br /><br />Basicamente, quando um FGF se liga à parte do FGFR3 que está fora da célula, ele ativa ("liga") o FGFR3 iniciando uma série de reações químicas que consistem em uma enzima ativando a vizinha e esta a seguinte como em uma cadeia de dominós, até a última, que entra no núcleo da célula (Figura 3). Dentro do núcleo da célula, esta última enzima ativará agentes locais que desencadearão (ou interromperão) a produção de proteínas a partir do DNA, cada uma delas com funções distintas. Nos condrócitos, os sinais provenientes do FGFR3 "dizem" ao núcleo da célula para interromper as atividades de multiplicação celular. Se os condrócitos param de se multiplicar, o crescimento ósseo fica comprometido (2,3).</span></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt">Figura 2. O FGFR3 é como uma antena no telhado da casa, captando sinais de fora da célula e entregando-os ao núcleo da célula.</span></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><br />Figura 3. Vias de sinalização do FGFR3.</span></span></span></div>
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<tr align="left"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">De <a href="https://www.nature.com/articles/boneres20143">Su N et al. Bone Res 2014; 2: 14003</a>. Reproduzido aqui apenas para fins educativos.</span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><br />Como você pode ver na Figura 3, a ativação do FGFR3 aciona várias cascatas enzimáticas (as vias sinalizadoras). A cascata MAPK (para Proteína Quinase Ativada por Mitógeno) é a mais importante para nós no contexto do CNP. A cascata MAPK consiste nas enzimas RAS, RAF, MEK e ERK (à direita na Figura 3) (3). A enzima ERK é a que alcança o núcleo da célula.<br /><br />Vários estudos estabeleceram que, sob a ativação do FGFR3, a MAPK é especialmente responsável por regular o aumento dos condrócitos (hipertrofia, ver Figura 1) (2,3). A zona hipertrófica parece ser a camada mais importante na placa de crescimento em relação ao crescimento ósseo. Sob a superativação do FGFR3 na acondroplasia, há menos condrócitos proliferando e aumentando e é aqui que o CNP tem um importante papel. Vamos ver como isso funciona.<br /><br /><i><b>CNP e FGFR3</b></i><br /><br />O CNP é produzido dentro da placa de crescimento e funciona como um promotor de crescimento ósseo, logo tem um efeito oposto ao FGFR3. Quando liberado, esse pequeno peptídeo se liga ao seu receptor na membrana celular dos condrócitos (da mesma forma que o FGF se liga ao FGFR3) e ativa uma via química dentro dos condrócitos que inibe a MAPK ao nível da enzima RAF (Figura 4) (2). Você consegue ver o ponto? O CNP trabalha naturalmente reduzindo a atividade da via FGFR3.<br /><br />Figura 4. Interseção das vias do FGFR3 e CNP.</span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">De<a href="https://academic.oup.com/hmg/article-pdf/25/R1/R2/7145150/ddv419.pdf"> Klag KA e Horton WA</a>. Hum Mol Gen 2016; 25: R2-R8. Reproduzida aqui apenas para fins educativos.</span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><br /><i><b>CNP e crescimento ósseo</b></i><br /><br />Mutações de perda de função no gene do CNP ou no receptor do CNP (chamado NPRB), que prejudicam sua função normal, causam uma displasia óssea genética muito rara chamada <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=acromesomelic+dysplasia+maroteaux+type"><i>displasia acromesomélica do tipo Maroteaux</i></a>, que tem algumas características que se assemelham à acondroplasia (4,5). Pelo contrário, as mutações que levam ao ganho em função do CNP ou seu receptor levam ao crescimento excessivo dos ossos (6,7). O papel do CNP no crescimento ósseo foi descrito também em modelos de camundongos com acondroplasia e de ausência de CNP (8).<br /><br /><i><b>Fazendo do CNP uma terapia viável para a acondroplasia</b></i><br /><br />A vida não é fácil para os peptídeos. Os processos da placa de crescimento são rigidamente regulados, como já vimos, mas na verdade isso ocorre em todos os processos orgânicos em funcionamento em nosso corpo. Proteínas e </span><span class="tlid-translation translation" lang="pt">peptídeos </span><span class="tlid-translation translation" lang="pt">ativos circulantes como o CNP podem iniciar, aumentar, diminuir ou interromper muitas reações químicas, de modo que o organismo possui vários sistemas para remover esses agentes da circulação, para evitar que causem efeitos indesejáveis. Um desses sistemas é composto por enzimas no sangue que têm como alvo peptídeos como o CNP (são chamadas de <i>endopeptidases </i>ou <i>endoproteases</i>). Isso é tão verdadeiro que, uma vez liberado na corrente sanguínea, o CNP durará apenas dois minutos (o que é chamado de meia-vida) (9).<br />Há cerca de dez anos atrás, cientistas provaram que o CNP tem um papel positivo no crescimento ósseo e que poderia contrabalançar o efeito inibitório do FGFR3 na acondroplasia (8), mas com essa curta meia-vida de apenas 2 min, como eles poderiam administrar o CNP para restaurar o crescimento ósseo? Eles foram capazes de mostrar que a infusão contínua de CNP teve um efeito positivo no crescimento ósseo (8), mas ter uma bomba de infusão conectada ao corpo para conseguir o efeito não parecia ser uma opção razoável quando se pensava em terapias de longo prazo naquele momento.<br /><br />Portanto, era preciso encontrar outras soluções. O CNP faz parte de uma família de três moléculas estreitamente relacionadas, denominadas <i>peptídeos natriuréticos</i>. Um deles, o <i>peptídeo natriurético do cérebro (brain)</i> (BNP) mostrou ser naturalmente mais resistente à endoproteases devido a uma "cauda" prolongada que o CNP não possui (Figura 5). Com esse conhecimento em mãos, os pesquisadores desenvolveram uma forma de CNP que </span>possui uma cauda prolongada similar ao BNP (10).<br /> <br />Figura 5. Peptídeos Natriuréticos.</span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /><span id="goog_1284140939"></span><span id="goog_1284140940"></span><br /><i><b>Desenvolvendo o vosoritide</b></i><br /><span class="tlid-translation translation" lang="pt"><br />O CNP modificado (chamado de análogo), que conhecemos com o nome de vosoritide (BMN-111), não apenas retém as funções biológicas do peptídeo original, mas também é mais resistente à destruição pelas enzimas neutralizadoras, com uma meia-vida prolongada de 20 minutos. Ser capaz de circular por mais tempo na corrente sanguínea deu tempo suficiente para que o vosoritide pudesse alcançar as placas de crescimento para exercer sua função esperada (10).<br /><br />De fato, ambos os estudos pré-clínicos em ratos e macacos resultaram em crescimento adicional e os resultados recentemente publicados do estudo de fase 2 em crianças com acondroplasia (10-12) demonstraram que uma injeção subcutânea (SC) uma vez ao dia de vosoritide resultou em aumento velocidade de crescimento ósseo e crescimento adicional em comparação com o que seria esperado sem o tratamento. O vosoritide está sendo testado em mais de 100 crianças em um estudo de fase 3 (<a href="https://www.clinicaltrials.gov/ct2/show/NCT03197766?term=NCT03197766&rank=1">NCT03197766</a>), com resultados que estarão disponíveis no final deste ano e, se bem-sucedido, o medicamento poderá estar no mercado no próximo ano.<br /><br />Agora, vamos dar uma olhada nos resultados do estudo da fase 2, publicado no New England Journal of Medicine (NEJM) na semana passada (12). Na verdade, os principais resultados relatados neste trabalho já haviam sido divulgados durante o evento "Dia da Pesquisa e Desenvolvimento" (R&D Day) realizado pela Biomarin em junho de 2018 e repetidos durante a conferência do JP Morgan em janeiro passado. Infelizmente, os links para essas apresentações não estão mais disponíveis no site da Biomarin, mas você pode ver um dos slides da apresentação do R&D Day de junho de 2018 na Figura 6.<br /><br />Figura 6. Efeito do vosoritide na velocidade média de crescimento após 42 meses na 3ª coorte do estudo de fase 2 (15mcg/kg). </span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">Imagem da apresentação do </span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">R&D Day</span> da Biomarin (Jun 2018).</span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt">O conteúdo do estudo de fase 2 é protegido por direitos autorais, então não posso reproduzir figuras publicadas na revista, mas o NEJM divulgou uma imagem em sua <a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1">conta no Twitter</a> mostrando um dos principais resultados do estudo (Figura 7).<br /><br />Figura 7. Aumento da velocidade de crescimento ósseo após seis meses do início do tratamento com vosoritide.</span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">De
<a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1813446"> Savararayan R et al. NEJM 2019</a>; imagem (correspondente à Figura 1A no
artigo original) obtida da <a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1">conta </a></span></span></span><a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">Twitter </span></span></span><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">de acesso aberto </span></span></span><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">do NEJM</span></span></span></a><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"> e
reproduzida aqui apenas para fins educativos.</span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><br />Em resumo, o vosoritide (15mcg/kg) foi capaz de restaurar a velocidade de crescimento ósseo em crianças </span><span class="tlid-translation translation" lang="pt">com acondroplasia tratadas a um nível </span><span class="tlid-translation translation" lang="pt">mais próximo da velocidade média de crescimento ósseo observada em crianças não afetadas (Figura 6). O efeito se manteve após 42 meses de exposição. Não posso mostrar aqui, mas em uma das figuras (Figura 1B no texto original) pode-se interpretar que há uma leve tendência a uma redução no efeito sobre o crescimento ósseo ao longo dos 42 meses (12).<br /><br />De todo modo, o estudo mostrou melhora progressiva no <i>escore z para altura</i> com 15mcg/kg/dia, o que, em linguagem do mundo real, significa que a diferença entre o padrão de crescimento das crianças expostas em relação às curvas de crescimento padrão diminuiu ao longo do tempo (12).<br /><br />Uma questão que foi levantada no início do desenvolvimento clínico do vosoritide anos atrás foi se a droga causaria o agravamento da desproporção do corpo. Os resultados deste estudo mostram que isso não aconteceu mas, por outro lado, não houve melhora significativa nesse aspecto da displasia (12). É preciso lembrar que a maior parte da desproporção é estabelecida nos dois primeiros anos de vida, e que as crianças neste estudo tinham pelo menos seis anos de idade no momento da inscrição, possivelmente tarde demais para ver efeitos relevantes neste aspecto da acondroplasia.<br /><br />Quanto a segurança, parece que o vosoritide tem um perfil de segurança razoável, com a maioria dos eventos adversos ligados à reações no local da injeção, que foram em sua maioria de intensidade leve. A exposição à substâncias biológicas pode desencadear uma resposta imunológica do organismo, que pode produzir anticorpos contra a droga administrada. Isso é comum no tratamento com anticorpos monoclonais contra o câncer e outras condições inflamatórias, por isso não é surpreendente que anticorpos anti-droga (ADA) tenham sido encontrados neste estudo (12). No entanto, parece que a presença de ADAs não teria impacto na eficácia do medicamento (13).<br /><br />Qual será a resposta para seguinte pergunta? Uma vez que os resultados dos 42 meses de exposição já estavam disponíveis há um ano, por que resultados além daquele ponto de corte não foram incluídos neste estudo, que acaba de ser publicado?</span></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><b><i>Existe algo a melhorar?</i></b><br /><br />Bem, o vosoritide tem mostrado consistentemente resultados que, se confirmados no estudo </span></span></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">de fase 3</span></span></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"> em andamento (<a href="https://www.clinicaltrials.gov/ct2/show/NCT03197766?term=NCT03197766&rank=1">NCT03197766</a>), podem abrir caminho para ser aprovado para o tratamento da acondroplasia no próximo ano. Esta é uma notícia maravilhosa, pois esta terapia pode ajudar a melhorar a qualidade de vida de muitas crianças no futuro. No entanto, parece que há espaço para efeitos de crescimento ósseo ainda melhores com o CNP.<br /><br />A <a href="https://ascendispharma.com/product-pipeline/transcon-cnp/">Ascendis Pharma</a> está desenvolvendo outro análogo do CNP (eles chamam de CNP-38, uma molécula de CNP com 38 aminoácidos), mas usando tecnologia proprietária para melhorar quanto tempo o seu CNP circula para exercer seus efeitos nos ossos. Eles criaram um sistema de transporte (podemos chamar de "táxi") para moléculas delicadas como o CNP (Figura 8). Protegido pelo táxi da Ascendis, o TransCon, seu CNP mostrou ter uma meia-vida muito mais longa em comparação com o vosoritide. De fato, eles acabaram de publicar os resultados completos de seus estudos pré-clínicos feitos com o TransCon CNP, que incluíram testes comparando seu CNP com o vosoritide (14). Em seu estudo eles reproduziram a molécula correspondente ao vosoritide, que é um CNP com 39 aminoácidos (ou, CNP-39) para comparar com seu CNP-38. Vamos dar uma olhada nesse estudo.<br /><br />Figura 8. Sistema de transporte TransCon.</span></span></span></span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiRiruwDgottafvCPf8iGalVdCo6X_n2cTC4ioEPuD0JiJ98GmfaCFlDDGDPuuGcPDRY51jau5tq3DmY_Wxq6KIxDAxmTbpzcUQBDIE-cz-njDuOfYCC0NH75t8jRij4A_S_cUhJMGRj9U/s1600/updated-transcon2.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="342" data-original-width="994" height="220" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiRiruwDgottafvCPf8iGalVdCo6X_n2cTC4ioEPuD0JiJ98GmfaCFlDDGDPuuGcPDRY51jau5tq3DmY_Wxq6KIxDAxmTbpzcUQBDIE-cz-njDuOfYCC0NH75t8jRij4A_S_cUhJMGRj9U/s640/updated-transcon2.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">Da Ascendis Pharma. Você pode ver mais <a href="https://ascendispharma.com/platform/transcon-technology/">aqui</a>.</span></span></span></span></span></span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">Em resumo, devido às características de seu táxi e sua estrutura de CNP, eles verificaram que seu sistema TransCon oferecia uma exposição estável do seu CNP por uma semana, sem o pico de dosagem no plasma observado com o vosoritide, portanto, com mínimo efeito sobre a pressão sanguínea. O efeito no crescimento ósseo foi pelo menos tão bom quanto com o CNP-39 (Figura 9) (14).<br /><br />Figura 9. Efeito do TransCon CNP (40 e 100 mcg/kg) vs. placebo e CNP-39 no comprimento do corpo e nos ossos.</span></span></span></span><br />
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<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">De
<a href="http://jpet.aspetjournals.org/content/early/2019/06/24/jpet.119.258251">Breinholt VA et al. </a>J Pharmacol Exp Ther 24 de junho de 2019,
jpet.119.258251 (Artigo de acesso livre). Reproduzido aqui apenas para
fins educativos. <b>Pos. Ctrl. = CNP-39</b>.</span></span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><br />A Ascendis já realizou um <a href="https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375353&isReview=true">estudo de fase 1</a> com o TransCon CNP em voluntários saudáveis e confirmou a longa meia-vida de seu análogo, o que permitirá uma dose semanal, em contraste com a dose diária de vosoritide. Não houve questões com segurança cardíaca. A Ascendis deve iniciar seu estudo de fase 2 em crianças em breve.<br /><br /><b><i>Este é o fim da história?</i></b><br /><br />Não, de forma alguma. A Daiichi Sankio, uma indústria farmacêutica japonesa, está desenvolvendo o ASB20123, um novo análogo do CNP. Neste caso, o composto é uma molécula de fusão onde a parte ativa do CNP é combinada com um fragmento do hormônio grelina, um outro peptídeo (Figura 10). Essa engenharia torna o CNP resistente à endopeptidases, dando mais tempo para que ele exerça suas funções (15,16). Basicamente, é o mesmo princípio usado para os análogos da Biomarin e da Ascendis.<br /><br />Figura 10. Estrutura do ASB20123, um novo análogo do CNP.</span></span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">De <a href="https://doi.org/10.1371/journal.pone.0212680">Morozumi N et al. PlosOne</a> 2019 </span></span></span></span><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">(acesso livre)</span></span></span></span>, reproduzido aqui apenas para fins educativos.</span></span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">O ASB20123 demonstrou efeitos positivos claros no crescimento ósseo, como visto em seus experimentos em seu modelo de rato (Figura 11). Observe na figura 11D que é possível que, sob a maior dose testada, possa ter ocorrido crescimento excessivo (o terceiro animal). Infelizmente, não há radiografias neste estudo que permitam verificar densidades ou formas ósseas, mas, de fato, os pesquisadores mencionam que o supercrescimento provavelmente ocorreu quando os animais receberam doses mais altas (16).<br /><br />Figura 11. Efeitos do ASB20123 no crescimento em um modelo de camundongo.</span></span></span></span></div>
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<tr align="justify"><td class="tr-caption"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: x-small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">Curvas
de crescimento de camundongos ICR juvenis fêmeas tratados com ASB20123
sc durante as 8 semanas do período de dosagem e as 4 semanas do período
de washout. Os dados do peso corporal (A), comprimento do corpo (B) e
comprimento da cauda (C) são mostrados nos painéis superiores, e as
fotografias no painel inferior representam a aparência grosseira dos
ratos no Dia 56 (D). Cada valor representa a média ± DP de 10 (para o
período de dosagem) ou 5 ratos (para o período de washout). NS: não
significativo (p> 0,05), *: diferença significativa (p <0,05) em
relação ao grupo controle pelo teste de <a href="https://doi.org/10.1371/journal.pone.0212680">Dunnett. De Morozumi N et al.</a>
PlosOne 2019 (acesso livre), reproduzido aqui apenas para fins
educativos.</span></span></span></span></td></tr>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><br />Os pesquisadores também testaram o ASB20123 através de uma bomba SC, novamente fornecendo uma liberação sustentada de seu análogo, com melhores resultados de crescimento. O argumento é que o uso de uma bomba SC pode permitir concentrações estáveis, porém menores, de seu análogo para promover o crescimento ósseo sem eventos adversos cardíacos (especialmente hipotensão) (16). Bombas SC mais novas parecem ser mais confortáveis do que os modelos mais antigos e poupariam as crianças de injeções diárias ou semanais. Não me sinto exatamente confortável com essa abordagem ainda, mas acho que é muito cedo para tirar conclusões sobre isso.</span></span></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><i><b>Horizonte brilhante</b></i><br /><br />O campo da terapia para a acondroplasia está ficando lotado. Agora, existem dois análogos de CNP em desenvolvimento clínico, um deles, vosoritide, mais próximo da aprovação para o mercado, aguardando resultados de seu estudo de fase 3 no final deste ano. O outro, TransCon CNP, segue para o estudo de fase 2. A Therachon está desenvolvendo o TA-46, uma molécula baseada no FGFR3 e projetada para competir </span></span></span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">pelos FGFs </span></span></span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">com o receptor mutante (17). Um grupo japonês vem trabalhando com a <i>meclizina</i>, um antigo medicamento antiemético que mostrou efeitos positivos no crescimento ósseo (18). A <a href="https://www.qedtx.com/achondroplasia/">QED Therapeutics</a>, uma pequena empresa de biotecnologia, começou a trabalhar com o <i>infigratinib</i>, uma molécula projetada para bloquear a ativação dos FGFRs (19). O grupo japonês da Daiichi Sankio acaba de apresentar seu análogo do CNP (16). A <i>osteocrina</i>, um peptídeo natural, mostrou melhorar o crescimento ósseo bloqueando o NPRC (um receptor regulador para peptídeos natriuréticos), dando mais tempo para o CNP exercer seus efeitos no crescimento ósseo (20). Investigadores descobriram que uma família de drogas usadas para baixar o colesterol, as <i>estatinas</i>, também pode ser usada para melhorar o crescimento ósseo na acondroplasia (21). Além disso, já existem pesquisas iniciais explorando edição genética para tratar a acondroplasia (a ser revisada em um artigo futuro).<br /><i><b><br />No entanto, isso ainda não é o fim</b></i><br /><br />Com o conhecimento crescente sobre as vias químicas alteradas na acondroplasia e as pesquisas para colocá-las em equilíbrio novamente, os pesquisadores também começaram a explorar o uso de terapias inicialmente projetadas para a acondroplasia em outras displasias esqueléticas onde as vias do FGFR podem ter um papel relevante. O exemplo mais natural é a hipocondroplasia, que também é causada por mutações no FGFR3. Mas existem outras iniciativas.<br /><br />Por exemplo, um estudo mostrou que o BMN111 (vosoritide) teve efeitos positivos em um modelo da Síndrome de Crouzon, uma craniossinostose associada a uma mutação do FGFR2 (22). A via da MAPK, chave na acondroplasia, também é fundamental na família de desordens genéticas denominadas RASopatias, nas quais enzimas da via MAPK ou seus reguladores têm mutações que prejudicam suas funções normais, o que causa uma infinidade de complicações clínicas. As RASopatias incluem a Neurofibromatose e a Síndrome de Noonan, entre vários outros distúrbios. Um trabalho recente com estatinas na Síndrome de Noonan mostrou que elas foram capazes de resgatar o crescimento nessa RASopatia (23). O mesmo grupo que trabalha com o ASB20123 testou o CNP em um modelo de rato com síndrome cardio-facio-cutânea, outra RASopatia, com resultados positivos (24).<br /><br />Há novidades ainda melhores. Alguns meses atrás, pesquisadores chineses publicaram um estudo no qual descobriram que o FGFR3 tem um papel importante no mecanismo de distúrbios genéticos ligados à mutações no gene <i>SLC26A2</i>, que incluem a <i>displasia diastrófica</i>. Eles mostraram que inibir o FGFR3 com o infigratinib (o bloqueador do FGFR em desenvolvimento pela QED) melhorou a formação óssea e os fenótipos de duas formas letais de distúrbios do <i>SLC26A2</i>: <i>acondrogênese tipo IB</i> e <i>atelosteogênese tipo II</i> (25). Se eles conseguiram melhorar os fenótipos naquelas formas devastadoras de desordens genéticas ligadas ao transporte de sulfato, quais seriam os resultados em formas menos severas, como a displasia diastrófica?<br /><br />A grande questão não é mais se há, ou haverá, qualquer tratamento disponível. A questão agora é: em que outras </span></span></span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">displasias esqueléticas </span></span></span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">terapias para a acondroplasia também poderão oferecer benefícios?<br /><br /><i><b>Divisão</b></i><br /><br />A comunidade interessada tem se dividido ultimamente com opiniões divergentes sobre quais são realmente os propósitos dessas novas </span></span></span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">potenciais </span></span></span><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt">terapias. Alguns afirmam que seriam apenas para efeitos cosméticos, e uma ameaça à diversidade humana. Uma torrente de acusações e julgamento severo sobre os pais tomarem decisões sobre seus filhos sem seu "consentimento" tem sido publicada nas mídias sociais, como se decisões não são o que os pais sempre tomam, todos os dias, das mais banais às mais complexas questões possíveis em relação aos seus filhos.<br /> </span></span></span></span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><span class="tlid-translation translation" lang="pt"><i><b>Abraçando a mudança</b></i><br /><br />Não muito tempo atrás, não havia nada a ser feito após o diagnóstico de uma desordem genética, porém resignar-se, pois não havia perspectivas à frente.<br /><br />Agora, o tempo para a resignação acabou. Terapias para desordens genéticas do crescimento ósseo estão a caminho e elas não têm nada a ver com a redução da diversidade humana, como alguns têm declarado ultimamente. Elas têm a ver com proporcionar uma vida melhor para as crianças afetadas, futuros adultos.<br /><br />Ao restaurar o crescimento ósseo, muitas complicações clínicas observadas em displasias ósseas poderão finalmente ser prevenidas ou minimizadas. Isso resultará em melhor funcionamento e melhor qualidade de vida para nossos amados filhos, à medida que crescem e se tornam adultos. Você pode imaginar seu filho não ter que passar por grandes cirurgias ainda bebê, ou ter que lidar com complicações ortopédicas e neurológicas ao longo da vida? (26, 27) Isso não seria bom o suficiente?<br /><br />E finalmente, se restaurar o crescimento ósseo na acondroplasia e em outras desordens ósseas tornará os indivíduos tratados mais altos, melhor ainda, pois eles serão capazes de enfrentar melhor os muitos desafios existentes no mundo lá fora</span></span></span><span class="tlid-translation translation" lang="pt"><span class="" title="">.</span> <span title="">Se você ainda não está lá, deve começar a pensar em abraçar a mudança logo.</span> <span title="">Ela está chegando.</span></span></span></span></div>
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<i><b><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">Referências</span></span></b></i></div>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> <br />1. <a href="https://www.ncbi.nlm.nih.gov/pubmed/12748651">Kronenberg HM</a>. Developmental regulation of the growth plate. Nature 2003;423 (6937):332–6.<br /> <br /> 2. <a href="https://academic.oup.com/hmg/article-pdf/25/R1/R2/7145150/ddv419.pdf">Klag KA and Horton WA.</a> Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Gen 2016; 25:R2-R8. Free access.<br /> <br /> 3. <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/dvdy.24479">Ornitz DM, Legeai-Mallet L</a>. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 2017; 246(4):291–309. Free access.<br /> <br /> 4. <a href="https://www.nature.com/articles/gim201766.pdf">Hisado-Oliva A et al</a>. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature.Genet Med 2018;20(1):91-7. Free access. <br /> <br /> 5. <a href="https://academic.oup.com/jcem/article-pdf/99/4/E713/9050688/jcemE713.pdf">Amano N et al.</a> Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. J Clin Endocrinol Metab 2014 Apr;99(4):E713-8. Free access. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 6. <a href="https://www.ncbi.nlm.nih.gov/pubmed/24259409">Miura K</a> et al. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A 2014;164A(1):156-63. <br /> <br /> 7. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25728306">Ko JM</a> et al. Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1). Am J Med Genet A 2015; 167A(5):1033-8. <br /> <br /> 8. <a href="https://www.jstage.jst.go.jp/article/endocrj/57/8/57_K10E-164/_pdf/-char/en">Yasoda A, Nakao K.</a>. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocr J 2010;57(8):659-66. Free access.<br /> <br />9.<a href="https://www.ncbi.nlm.nih.gov/pubmed/8200946"> Hunt PJ et al</a>. Bioactivity and metabolism of C-type natriuretic peptide in normal man. J Clin Endocrinol Metab 1994; 78: 1428-35. <br /> <br /> 10. <a href="https://www.cell.com/action/showPdf?pii=S0002-9297%2812%2900537-X">Lorget F et al</a>. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet 2012; 91(6):1108–14. Free access.<br /> <br /> 11. <a href="http://jpet.aspetjournals.org/content/jpet/353/1/132.full.pdf">Wendt DJ et al</a>. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther 2015;353:132–49. Free access.<br /> <br /> 12. <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1813446">Savarirayan R et al</a>. C-type natriuretic peptide analogue therapy in children with achondroplasia. NEJM June 18, 2019. DOI: 10.1056/NEJMoa1813446. Published ahead of print.<br /> <br /> 13. <a href="https://isds2019.exordo.com/programme/presentation/283">Chan D et al.</a> Pharmacokinetic and exposure-response analysis of vosoritide in children with achondroplasia. Abstract. To be presented at the ISDS 2019 Meeting, Oslo, Norway, Sep 12, 2019. Acesso livre.<br /><br />14.<a href="http://jpet.aspetjournals.org/content/jpet/early/2019/06/24/jpet.119.258251.full.pdf"> Breinholt VA et al.</a> TransCon CNP, a sustained-release C-Type Natriuretic Peptide prodrug, a potentially safe and efficacious new therapeutic modality for the treatment of comorbidities associated with FGFR3-related skeletal dysplasias. J Pharmacol Exp Ther June 24, 2019, jpet.119.258251. Published ahead of print. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span> <br /> 15. <a href="https://www.ncbi.nlm.nih.gov/pubmed/28899838">Morozumi N et al</a>. Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties. Peptides 2017;97:16-21. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span> <br /> 16.<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680#pone-0212680-g007"> </a><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680#pone-0212680-g007">Morozumi N et al</a>. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoS One 2019 Feb 22;14(2):e0212680. </span></span><br /><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">17. <a href="https://stm.sciencemag.org/content/5/203/203ra124/tab-pdf">Garcia S et al</a>. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Sci Transl Med 2013 Sep 18;5(203):203ra124. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span> <br />18. <a href="https://www.nature.com/articles/s41598-017-07044-8.pdf">Matsushita M</a>. Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia. Sci Rep 2017;7(1):7371. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span> <br /> 19. <a href="https://www.jci.org/articles/view/83926/pdf">Komla-Ebri D et al</a>. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016;126(5):1871-84. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span> <br /> 20. <a href="https://www.jci.org/articles/view/94912/pdf">Kanai Y et al</a>. Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance. J Clin Invest 2017;127(11):4136-47. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span> <br /> 21. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al</a>. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 2014; 513(7519):507-11. </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 22. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201492">Holmes G et al</a>. C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=natriuretic+peptdie+crouzon+syndrome#">PLoS One.</a> 2018;13(7):e0201492. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span> <br /> 23.<a href="https://academic.oup.com/hmg/article-pdf/27/13/2276/25061148/ddy133.pdf">Tajan M et al</a>. Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth. Hum Mol Genet 2018;27(13):2276-89. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span> <br /> 24. <a href="https://www.ncbi.nlm.nih.gov/pubmed/30239744">Inoue SI et al</a>. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome. Hum Mol Genet 2019; 28(1):74-83. <br /> </span></span></div>
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">25. <a href="https://www.ebiomedicine.com/article/S2352-3964(19)30010-6/pdf">Zheng C et al</a>. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 2019;40:695-709. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">26. <a href="https://www.ncbi.nlm.nih.gov/books/NBK1152/">Pauli RM, Legare JM</a>. Achondroplasia. 2018. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span> </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br /> 27. <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.13542">Fredwall SO et al</a>. Current knowledge of medical complications in adults with achondroplasia: A scoping review. Clin Genet. 2019 Mar 27. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Acesso livre.</span></span></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"> </span></span></span></span><br /> </span></span><span class="tlid-translation-gender-indicator translation-gender-indicator"></span></div>
Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-31374406073527498702019-06-29T13:38:00.002-04:002023-04-28T07:51:32.776-04:00Treating achondroplasia: CNP under the spotlight<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Extra, Extra! </b></i> </span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">I can tell you. There are so many news recently published about </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i>C-type natriuretic peptide</i> (</span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">CNP) for achondroplasia and other skeletal conditions that it is hard for me to choose where to start from.<i><b> </b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>But, wait a minute... </b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">I know, I know, all we want to talk is about CNP</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"></span>. But b</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">e patient as I believe that a bit of background information</span></span> </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">can make it easier to understand CNP, <i>fibroblast growth factor receptor 3</i> (FGFR3) and achondroplasia and how to put all the new information in context. So, </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">let's start with a brief review of how bones grow.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>H</b><b>ow bones grow</b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">As the seventeen readers of this blog know, bone growth is a long, structured and very complex process that occurs during the development of a child through adulthood. Influenced by dozens of local and systemic agents, the bone growth process could be seen as a Mozart's symphony, where many different instruments play together in perfect harmony to create wonderful art. If you stop to think about it, what is on stake and how it is achieved, you would conclude that it is a piece of natural miracle. Every single player in the growth process works in fine tuning to achieve what is planned in our DNA.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Our long bones grow from thin cartilage layers located in their extremities called <i>growth plates</i>. Within the growth plates, <i>chondrocytes</i>, the master cells of bone growth, will "wake up" from a dormant state, start a proliferating frenzy, become very enlarged and, in the end of their life cycle, will give place to osteoblasts, the bone builder cells </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">(Figure 1)</span></span> </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">(1)</span></span>. As said above, this process is regulated by many local and systemic agents. When they are not in balance, the normal process is compromised either leading to stunted or to excessive bone growth.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 1. Growth plate.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>What happens in achondroplasia </b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">In achondroplasia, FGFR3, one of the local agents that regulate how chondrocytes wake up, proliferate and enlarge, is working too much due to a mutation in its structure (2,3). Since the normal action of FGFR3 is to reduce chondrocyte proliferation and hypertrophy (enlargement) pace, when it is working excessively chondrocytes just stop their normal functions and bone growth is severely compromised.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">FGFR3 is what is called a receptor enzyme. It is placed across the chondrocyte cell membrane, just like an antenna on top of the house roof (Figure 2). While a TV antenna will capture TV signals to deliver them to our TVs inside home, FGFR3 transmits chemical messages delivered by FGFs from outside the cell to the cell nucleus. </span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Basically, when a FGF binds to the part of FGFR3 that is outside the cell, it activates (turns on) FGFR3 starting a series of chemical reactions consisting of an enzyme activating the next one and further like in a domino chain, until the last one enters the cell nucleus (Figure 3). Inside the cell nucleus, this last enzyme will turn on local agents that will trigger (or stop) the production of proteins from the DNA, each of them with distinct functions. In chondrocytes, the signals coming from FGFR3 "tell" the cell nucleus to stop cell multiplying activities. If chondrocytes stop multiplying, bone growth is compromised (2,3).</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 2. FGFR3 is like a roof antenna, picking up signals from outside the cell and delivering them to the cell nucleus.</span></span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgN34_DpUgGJaxBYyUPFfNOkVi2IV1KdzGuJ6j417-Tlr9OcUhee-KOhniqzPkvxF8dolYBs5yIgpW4rhLDUMVu9sHFfmGgf51NJirMugJ4dd3icVdu0qLdobTYy4dlxhWp6c_KW5MOYL0/s1600/AntennaFGFR3b.JPG" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="612" data-original-width="1600" height="244" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgN34_DpUgGJaxBYyUPFfNOkVi2IV1KdzGuJ6j417-Tlr9OcUhee-KOhniqzPkvxF8dolYBs5yIgpW4rhLDUMVu9sHFfmGgf51NJirMugJ4dd3icVdu0qLdobTYy4dlxhWp6c_KW5MOYL0/s640/AntennaFGFR3b.JPG" width="640" /></a></div>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 3. FGFR3 signaling pathways.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEirQ5yZDFf_gN9pjMh9lM8-B2Do4u7ea0mrKN7vpQNKGo-cOCsZWM5JD1NxPCMNPoW_V7tiuhlx_Q5Z0qr5YkoPd5jyLzCEUxLylBvHlsL-dFf5dVmhmwnCE1iK7UTds_a2MeWgPMFWjYE/s1600/FGFR3+cascade+2b.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="708" data-original-width="929" height="486" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEirQ5yZDFf_gN9pjMh9lM8-B2Do4u7ea0mrKN7vpQNKGo-cOCsZWM5JD1NxPCMNPoW_V7tiuhlx_Q5Z0qr5YkoPd5jyLzCEUxLylBvHlsL-dFf5dVmhmwnCE1iK7UTds_a2MeWgPMFWjYE/s640/FGFR3+cascade+2b.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: x-small;">From<a href="https://www.nature.com/articles/boneres20143"> Su N et al. Bone Res 2014; 2: 14003</a>. Reproduced here for educational purposes only.</span></span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">As you see in Figure 3, FGFR3 activation turns on several enzymatic cascades. The MAPK (for Mitogen-Activated Protein Kinase) cascade is the important one for us in the context of CNP. The MAPK cascade consists of the enzymes RAS, RAF, MEK and ERK (at the right in Figure 3) (3). ERK is the one which goes to the nucleus.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Several studies established that </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">under FGFR3 activation </span></span>MAPK is specially responsible for regulating the enlargement of chondrocytes (hypertrophy, see Figure 1) (2,3). The hypertrophic zone seems to be the most important layer in the growth plate in regards to bone growth. Under FGFR3 overactivation in achondroplasia, there are fewer chondrocytes proliferating and enlarging and it is here where CNP has a role. Let's see how it works. </span></span><br />
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<i><b><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">CNP and FGFR3</span></span></b></i><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">CNP is produced within the cartilage growth plate and works as a bone growth promoter, so it has the opposite effect of FGFR3. When released, this small peptide binds its receptor on the chondrocyte cell membrane (just like FGFR3) and activates (turns on) a chemical pathway inside the chondrocyte that inhibit MAPK at the level of RAF (Figure 4) (2). Do you get the point? CNP works naturally reducing the activity of the FGFR3 pathway.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 4. FGFR3 and CNP crosstalk.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgWqta2hJM2EJZnkNlOwZ64gjthpoHSJgax1RajjH4fX5ZycEf4_kXTO6pvKu8D_285glMjQrVdZh1eMrDFaT5QqTWkHBnrveq5QpvZDB_9QW6vKegDZ3DhheuwEXyPQ_eL7GFowV3JYHI/s1600/william-horton+FGFR3_CNP+crosstalkb.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="412" data-original-width="560" height="292" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgWqta2hJM2EJZnkNlOwZ64gjthpoHSJgax1RajjH4fX5ZycEf4_kXTO6pvKu8D_285glMjQrVdZh1eMrDFaT5QqTWkHBnrveq5QpvZDB_9QW6vKegDZ3DhheuwEXyPQ_eL7GFowV3JYHI/s400/william-horton+FGFR3_CNP+crosstalkb.jpg" width="400" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-size: x-small;">From <a href="https://academic.oup.com/hmg/article/25/R1/R2/2355966">Klag KA and Horton WA. Hum Mol Gen 2016; 25:R2-R8</a>. Reproduced here for educational purposes only.</span></span></span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>CNP and bone growth </b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Loss-of-function mutations in the CNP gene or in the CNP receptor (called NPRB) that impair their normal function cause a very rare genetic bone dysplasia called <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=acromesomelic+dysplasia+maroteaux+type"><i>acromesomelic dysplasia Maroteaux type</i></a>, which has some features resembling achondroplasia (4,5). On the contrary, mutations leading to gain-in-function lead to bone overgrowth (6,7). The role of CNP in bone growth was further described in </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">achondroplasia and CNP-null </span></span>mouse models (8).</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Turning CNP into a viable therapy for achondroplasia</b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Life is not easy for peptides. The growth plate processes are tightly regulated, as we have already learned, but in fact this is true for all organic processes running in our body. Circulating active proteins and peptides like CNP can initiate, increase, decrease or stop many chemical reactions so the body has several systems to clear these agents off the circulation to avoid them to cause undesirable effects. One of these systems is comprised by blood enzymes that target peptides like CNP (they are called endopeptidases or endoproteases). This is so true that once released in the blood stream, CNP will last for about only two minutes (what is called half-life) (9).</span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Around ten years ago, scientists had proved that CNP has a positive role in bone growth and that it could counteract the inhibitory effect of FGFR3 in achondroplasia (8), but with that short half-life of just 2 min, how would they manage giving CNP to restore bone growth? They were able to show that continuous infusion of CNP had a positive effect on bone growth (8), but having an infusion pump connected to the body did not seem to be a reasonable option when thinking about long term therapies at that time.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Therefore, there might be other solutions out there. CNP is part of a family of three closely related molecules called <i>natriuretic peptides</i>. One of them, the <i>brain natriuretic peptide</i> (BNP) was shown to be naturally more resistant to endoproteases due to a prolonged "tail" that CNP does not have (Figure 5). With this knowledge in hand, researchers developed a form of CNP which bears a prolonged tail similar to BNP (10).</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 5. Natriuretic peptides.</span></span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjfZa_8adP1A5HP8gTbcXqwls9VZPP5wGxpJ5Z5v8LJhHU8JgDaFVre6YYLhHJXfVoom8D-IrkrgrQrfmP7ohYqNuLryiD3_Q-VqEo-lcznRZ0DaKhXCVLVVYxOloysmajmgxRaZGzV0oY/s1600/NatriureticPeptides2.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="257" data-original-width="1280" height="80" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjfZa_8adP1A5HP8gTbcXqwls9VZPP5wGxpJ5Z5v8LJhHU8JgDaFVre6YYLhHJXfVoom8D-IrkrgrQrfmP7ohYqNuLryiD3_Q-VqEo-lcznRZ0DaKhXCVLVVYxOloysmajmgxRaZGzV0oY/s400/NatriureticPeptides2.jpg" width="400" /></a></div>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Developing vosoritide </b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">The modified CNP (called analogue), which we know by the name of <i>vosoritide</i> (BMN-111), not only retains the biological functions of the original peptide but also is more resistant to neutralization by the clearance enzymes, with a prolonged half-life of 20 minutes. Being able to circulate longer in the blood stream gave enough time to vosoritide to reach the growth plates to exert its expected function (10).</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">In fact, both pre-clinical studies in mice and monkeys resulted in additional growth and the recently published results of the phase 2 study in children with achondroplasia (10-12) demonstrated that once-daily subcutaneous (SC) injection of vosoritide resulted in increased bone growth velocity and additional growth compared to what would be expected without the treatment. </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Vosoritide is now being tested in more than 100 children in </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">a
phase 3 study (</span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><a href="https://www.clinicaltrials.gov/ct2/show/NCT03197766?term=NCT03197766&rank=1">NCT03197766</a>), with results to be available by the end of this year and, if
successful, the drug could be on the market next year. </span></span></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Now, let's take a look on the results of the phase 2 study, just published in the New England Journal of Medicine (NEJM) last week (12). </span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Actually,
the main results reported in this paper had already been released
during the R&D Day event held by Biomarin in June 2018 and repeated during the JP Morgan conference on last January. Unfortunately, the links to those presentations are no longer available at the Biomarin's site but you can see a snapshot of the R&D Day presentation from June 2018 in Figure 6.</span></span></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 6. Effect of vosoritide in average growth velocity after 42 months in the 3rd cohort of the phase 2 trial (15mcg/kg).</span></span></span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiaEFxTXGmUusNensgVQBNkrXX9dHWToBdCaWQGj8fbqE33HS1FRKRx8q3l46jNwlQ39mxCw-zVxnj3nx0VaQ5MWmR4R9ZSG0svbDqe47gwywGrt06Qy5SnumbpNY8CSP86qF7d3J2VrHI/s1600/BiomarinR%2526D+Day+Slide+42+month+growth.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="532" data-original-width="708" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiaEFxTXGmUusNensgVQBNkrXX9dHWToBdCaWQGj8fbqE33HS1FRKRx8q3l46jNwlQ39mxCw-zVxnj3nx0VaQ5MWmR4R9ZSG0svbDqe47gwywGrt06Qy5SnumbpNY8CSP86qF7d3J2VrHI/s640/BiomarinR%2526D+Day+Slide+42+month+growth.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span face=""trebuchet ms" , sans-serif"><span style="font-size: x-small;">Snapshot from Biomarin's R&D Day presentation (Jun 2018).</span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">The phase 2 study paper contents are protected by copyright but the NEJM released a picture in their <a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1">Twitter account</a> showing one of the main results of the trial (Figure 7).</span></span></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 7. Increase of bone growth velocity after six months of starting treatment with vosoritide.</span></span></span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhvs5VAmQaNq6FOS1ge8_j31d15DMLhYXgaOrZa0cgPLA42yuAOtIEALuPxzs5MTxwOTgCWmAVKU1GfSYHkRjaOZ0ZmABpCQqq2t0bwsUghISc5BA4CgTaiEqTecKCtaQbu9MiP0I-BiRw/s1600/SavarirayanGrowthVelocNEJM2019b.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="297" data-original-width="698" height="272" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhvs5VAmQaNq6FOS1ge8_j31d15DMLhYXgaOrZa0cgPLA42yuAOtIEALuPxzs5MTxwOTgCWmAVKU1GfSYHkRjaOZ0ZmABpCQqq2t0bwsUghISc5BA4CgTaiEqTecKCtaQbu9MiP0I-BiRw/s640/SavarirayanGrowthVelocNEJM2019b.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif">From <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1813446">Savararayan R et al. NEJM 2019</a>; image (corresponding to Figure 1A in the original article) obtained from <a href="https://twitter.com/NEJM/status/1140924662194589697/photo/1">NEJM's Twitter open access account</a> and reproduced here for educational purposes only.</span></span></span></span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">In summary, vosoritide (15mcg/kg) was able to restore bone growth velocity in exposed children with achondroplasia closer to the average bone growth velocity seen in non-affected children (Figure 6). The effect was sustained after 42 months of exposure. I cannot display it here but in one of </span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">the picture</span></span></span><span style="font-size: small;">s (Figure 1B in the original text) one could interpret that there is what it seems to be a slight trend to a reduction on the effect on bone growth over the 42 months (12). </span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Nevertheless, the study showed progressive improvement on the z-score for height with 15mcg/kg/day which, in real world language, means that the difference of the exposed children growth pattern compared to the standard growth curves decreased overtime (12). </span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">One question that was raised in the beginning of the clinical development of vosoritide years ago was whether the drug would cause worsening of the body disproportion. Results from this study show that this was not the case, but by the other side, there was no significant improvement on this aspect of the dysplasia (12). Bear in mind that most of the disproportion is set in the first two years of life, and that the children in this study were at least six years-old on enrollment, possibly too late to see relevant effects in this aspect of achondroplasia. </span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">On the safety side, it seems that vosoritide has a fair safety profile, with the majority of adverse events linked to injection site reactions, which were mostly mild in intensity. Exposure to biologicals may trigger an immune response by the body, which may produce antibodies against that drug. This is common in the treatment with monoclonal antibodies against cancer and other inflammatory conditions, so it is not surprising that anti-drug antibodies (ADA) were found in this study (12). However, it seems that the presence of ADAs would not have had an impact in the drug efficacy (13).</span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">A question waiting answer: given that results from the 42 months of exposure were already available one year ago, why were results from beyond that cutoff not included in this study, which has just been published? </span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Is there space for improvement?</b></i></span></span></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Well, vosoritide has been consistently showing results that, if confirmed in the ongoing phase 3 study </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">(</span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><a href="https://www.clinicaltrials.gov/ct2/show/NCT03197766?term=NCT03197766&rank=1">NCT03197766</a>)</span></span></span></span>, may pave the way to be approved for the treatment of achondroplasia in the next year or so. These are wonderful news, as this therapy may help improving the quality of life of many children in the future. However, it seems that there is space for even better bone growth effects with CNP.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><a href="https://ascendispharma.com/product-pipeline/transcon-cnp/">Ascendis Pharma</a> is developing another CNP analogue (they call CNP-38 meaning a CNP molecule with 38 aminoacids) but using proprietary technology to improve how long their CNP circulates to exert its effects in the bones. They have created a carrier system (we can call it a transport or "taxi") for delicate molecules like CNP</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"> (Figure 8)</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">. Protected by Ascendis taxi, TransCon, their CNP was shown to have a much longer half-life compared to vosoritide. In fact, they have just published the complete results of their pre-clinical studies made with TransCon CNP, which included tests comparing their CNP with vosoritide (14). As a matter of information, in their study they have reproduced the molecule corresponding to vosoritide, which is a CNP with 39 aminoacids (</span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">thus CNP-39)</span></span> to compare with their CNP-38. Let's take a look on their study.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 8. TransCon carrier system.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiRiruwDgottafvCPf8iGalVdCo6X_n2cTC4ioEPuD0JiJ98GmfaCFlDDGDPuuGcPDRY51jau5tq3DmY_Wxq6KIxDAxmTbpzcUQBDIE-cz-njDuOfYCC0NH75t8jRij4A_S_cUhJMGRj9U/s1600/updated-transcon2.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="342" data-original-width="994" height="220" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiRiruwDgottafvCPf8iGalVdCo6X_n2cTC4ioEPuD0JiJ98GmfaCFlDDGDPuuGcPDRY51jau5tq3DmY_Wxq6KIxDAxmTbpzcUQBDIE-cz-njDuOfYCC0NH75t8jRij4A_S_cUhJMGRj9U/s640/updated-transcon2.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif">From Ascendis Pharma. You can learn more <a href="https://ascendispharma.com/platform/transcon-technology/">here</a>.</span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">In brief, due to the characteristics of their taxi and their CNP structure, they found that their TransCon system provided stable exposure of their CNP for a week, without the plasma peak observed with vosoritide, so with minimal if any effect on blood pressure. The effect in bone growth was at least as good as with CNP-39 (Figure 9) (14).</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 9. Effect of TransCon CNP (40 and 100 mcg/kg) vs. placebo and CNP-39 on body length and bones.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglwLCf_dA6wCXLas7YJ0xzYc_w-LwSSR5NwJXqRkkU9sAcL9yVW_mUPBAK6xx4UE2t3nnkOcqzQmuC7UgLLN4ApGQ-09Krs8_7LUGDqJscIm738HIzLjzCNG19OaHfF7Da692LB12gb1Q/s1600/BernholtAscendisTransConCNPEffectBones2019.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="593" data-original-width="820" height="460" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglwLCf_dA6wCXLas7YJ0xzYc_w-LwSSR5NwJXqRkkU9sAcL9yVW_mUPBAK6xx4UE2t3nnkOcqzQmuC7UgLLN4ApGQ-09Krs8_7LUGDqJscIm738HIzLjzCNG19OaHfF7Da692LB12gb1Q/s640/BernholtAscendisTransConCNPEffectBones2019.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif">From <a href="http://jpet.aspetjournals.org/content/early/2019/06/24/jpet.119.258251">Breinholt VA et al.</a> J Pharmacol Exp Ther <span class="highwire-cite-metadata-date highwire-cite-metadata">June 24, 2019, </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">jpet.119.258251. (</span></span></span><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif"><span class="highwire-cite-metadata-pages highwire-cite-metadata"><i>Open access article)</i>. </span></span></span><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif"><span class="highwire-cite-metadata-pages highwire-cite-metadata">Reproduced here for educational purposes only. </span></span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Ascendis has already conducted a <a href="https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375353&isReview=true">phase 1 study</a> with TransCon CNP in healthy volunteers, and they confirmed the long half-life of their analogue, which will allow a weekly dose, in contrast with the daily dose of vosoritide. There were no cardiac safety concerns. Ascendis should be starting their phase 2 study in children soon.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Is this the end of the story?</b></i></span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">No, not at all as Daiichi Sankio, a Japanese pharma industry, is developing ASB20123, a new analogue of CNP. In this case, the compound is a fusion molecule where the active part of CNP is combined with a fragment of the peptide hormone ghrelin </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">(Figure 10)</span></span>. This engineering makes CNP resistant to endopeptidases giving more time for it to exert its functions (15,16). Basically, it is the same principle used for Biomarin's and Ascendis' analogues.</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 10. Structure of ASB20123, a new CNP analogue.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhgXgaSp23eHYXrkAoWe_1KtF9nXOYZTu5hk4L4KI36Me6QixqlVI7HnQfebv0_dHTjfmB-uve7f0F7vzuOlvusyPQPLuejArdS_qZa6E3_ByBKoBBRAyyHZ0b46PLJJQfZ1D9uOBJiKkQ/s1600/ASB20123.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="731" data-original-width="1600" height="292" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhgXgaSp23eHYXrkAoWe_1KtF9nXOYZTu5hk4L4KI36Me6QixqlVI7HnQfebv0_dHTjfmB-uve7f0F7vzuOlvusyPQPLuejArdS_qZa6E3_ByBKoBBRAyyHZ0b46PLJJQfZ1D9uOBJiKkQ/s640/ASB20123.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif">From <a href="https://doi.org/10.1371/journal.pone.0212680">Morozumi N et al. PlosOne 2019</a>, reproduced here for educational purposes only.</span></span></td></tr>
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"> ASB20123 demonstrated clear positive effects in bone growth as seen in their experiments in their mouse model (Figure 11). Note that it is possible that under the highest dose tested it might have occurred overgrowth. Unfortunately, there are no radiographs in this study allowing to check bone densities or shapes but, in fact, the researchers mention that overgrowth likely occurred when the animals were given higher doses (16).</span></span><br />
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<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Figure 11. ASB20123 effects in growth in a mouse model.</span></span><br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhyQ9SnW6zvz29yMfG1QAgEG9V2-reVQyEjnHE7AcTcaPs4ndSggcc9ud7BA5NCxlwBlJtbIHByIcunbzYT3faTS6H1FdUoLVkLDc8QNdWYL6oXa0Xb4vsrZYgvqGl8PRRZvj4nrOwoN1U/s1600/ASB20123growtheffects.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="1039" data-original-width="1440" height="459" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhyQ9SnW6zvz29yMfG1QAgEG9V2-reVQyEjnHE7AcTcaPs4ndSggcc9ud7BA5NCxlwBlJtbIHByIcunbzYT3faTS6H1FdUoLVkLDc8QNdWYL6oXa0Xb4vsrZYgvqGl8PRRZvj4nrOwoN1U/s640/ASB20123growtheffects.jpg" width="640" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif"><span id="figure-title">Growth curves of female juvenile ICR mice treated with ASB20123 <i>sc</i> during the 8 weeks of the dosing period and the 4 weeks of the washout period.</span>
Body weight (A), body length (B) and tail length (C) data are
shown in the upper panels, and the photographs in the lower panel
represent the gross appearance of mice at Day 56 (D). Each value
represents the mean ± SD of 10 (for the dosing period) or 5 mice (for
the washout period). NS: not significant (<i>p</i> > 0.05), *: significant difference (<i>p</i> < 0.05) compared to the control group using Dunnett’s test.
</span></span><span style="font-size: x-small;"><span face=""trebuchet ms" , sans-serif">From <a href="https://doi.org/10.1371/journal.pone.0212680">Morozumi N et al. PlosOne 2019</a> (open access), reproduced here for educational purposes only.</span></span></td></tr>
</tbody></table>
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">The researchers also tested ASB20123 given through a SC pump, again providing sustained release of their analogue, with improved growth results. The argument is that the use of a SC pump may allow stable but lower concentrations of their analogue to promote bone growth without cardiac adverse events (especially hypotension) (16). Newer SC pumps seem to be more comfortable than older models and would spare children to have daily or weekly shots. I don't feel exactly comfortable about this approach yet but I think it is too early to draw conclusions about it.</span></span><br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><br /></span></span>
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>Bright horizon</b></i></span></span><br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><br /></span></span>
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">The achondroplasia therapy landscape is becoming crowded. Now, there are two CNP analogues in clinical development, one of them, vosoritide, closer to marketing approval, pending results from their phase 3 study in the end of this year. The other, TransCon CNP, heading to phase 2. Therachon is developing TA-46, a molecule based on FGFR3 and designed to compete against the mutated receptor for the FGFs (17). A Japanese group has been working with <i>meclizine</i>, an old antiemetic drug that showed positive effects on bone growth (18). <a href="https://www.qedtx.com/achondroplasia/">QED Therapeutics</a>, a small biotech, started working with <i>infigratinib</i>, a molecule designed to block FGFR activation (19). The Japanese group from Daiichi Sankio has just introduced their CNP analogue (16). <i>Osteocrin</i>, a natural peptide, has shown to improve bone growth by blocking NPRC (a trap receptor for natriuretic peptides) rendering more time to CNP to exert its effects in bone growth (20). Investigators have also found that a family of drugs used to lower cholesterol, the <i>statins</i>, may also be used to improve bone growth in achondroplasia (21). Furthermore, there is already initial research exploring gene editing to treat achondroplasia (to be reviewed in a future article).</span></span><br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><br /></span></span>
<i><b><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">However, this is still not the end</span></span></b></i><br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><br /></span></span>
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">With the mounting knowledge about the chemical pathways altered in achondroplasia and the research to put them in balance again, researchers have also started to explore the use of therapies initially designed for achondroplasia in other skeletal dysplasias where the FGFR pathways may have a relevant role. The most natural example is hypochondroplasia, which is also caused by mutations in FGFR3. But there are other initiatives.</span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">For instance, </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">a study showed that BMN111 (vosoritide) had positive effects in a model of Crouzon Syndrome, a craniosynostosis linked to a FGFR2 mutation (22).</span></span> The MAPK pathway, key in achondroplasia, is also fundamental in the family of genetic disorders called RASopathies, in which enzymes of the MAPK pathway or their regulators have mutations impairing their normal functions, which causes a plethora of clinical complications. The RASopathies include Neurofibromatosis and Noonan Syndrome among several other disorders. A recent work with statins in Noonan Syndrome showed that they were able to rescue growth in that RASopathy (23). The same group working with ASB20123 tested CNP in a mouse model of </span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">cardio-facio-cutaneous syndrome, another RASopathy, with positive results (24).</span></span><br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><br /></span></span>
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;">Things are getting better. A few months ago, Chinese investigators published a study where they found that FGFR3 has an important role in the mechanism of genetic disorders linked to mutations in the gene </span></span><i><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">SLC26A2</span></span></span></i><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">, which include <i>diastrophic dysplasia</i>. They showed that inhibiting FGFR3 with infigratinib (the FGFR blocker in development by QED) improved bone formation and the phenotypes of two lethal forms of <i>SLC26A2</i> disorders: </span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">achondrogenesis type IB and atelosteogenesis type II (25). If they were able to ammeliorate the phenotypes in those devastating forms of genetic disorders linked to sulphate transport, what would be the results in milder forms such as </span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">diastrophic dysplasia? </span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">The big question is not anymore if there is, or will be, any treatment available. The question now is: in which other skeletal dysplasias therapies for achondroplasia could also provide benefit?</span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><i><b>Division</b></i></span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">The interested community has been divided lately with diverging opinions about what these new potential therapies' purposes "really" are. Some claim that they would be just cosmetic, a threat to human diversity. A flow of accusations and harsh judgement over parents taking decisions about their children without their "consent" is being </span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">published in the social media</span></span></span></span></span></span>, as decisions are not what parents always take, </span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">every single day, </span></span></span></span></span></span>from the most banal to the most fundamental issue (whatever they are). </span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><i><b>Embracing the change </b></i></span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">Not long ago, </span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">there was nothing to be done after </span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">a diagnosis of a genetic disorder, but to resign, as there were no perspectives ahead. </span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">Now, the time for resignation is over. </span></span></span></span></span></span></span></span></span></span></span></span>Therapies for genetic bone growth disorders are on their way and they have nothing to do with reducing human diversity as some have been declaring lately. They have to do with providing a better life for affected children, future adults.</span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">By restoring bone growth, many clinical complications seen in skeletal dysplasias may finally be prevented or minimized. This will result in </span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">better functioning and </span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">better quality of life for our beloved children as they grow up to become adults. Can you imagine your kid not having to undergo major surgeries at young age, or having to deal with life-long orthopedic and neurological complications? (26, 27) Wouldn't that be good enough?</span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">And finally, if restoring bone growth in achondroplasia and other bone disorders will make treated individuals taller, even better, for they will be able to better face the many existent challenges in the world outside. If you are still not there yet, you should start thinking in e</span></span></span></span></span></span><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;">mbracing the change. It is coming.</span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span></span><br />
<br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span style="font-weight: normal;"> </span> </span></span><br />
<span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><i><b>References</b></i></span></span><br />
<br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">1. <a href="https://www.ncbi.nlm.nih.gov/pubmed/12748651">Kronenberg HM</a>. Developmental regulation of the growth plate. Nature 2003;423 (6937):332–6.</span></span><br />
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">2. <a href="https://academic.oup.com/hmg/article-pdf/25/R1/R2/7145150/ddv419.pdf">Klag KA and Horton WA.</a> Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Gen 2016; 25:R2-R8. <i>Free access.</i></span></span><br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><br /></span></span>
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">3. <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/dvdy.24479">Ornitz DM, Legeai-Mallet L</a>. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 2017; 246(4):291–309. <i>Free access.</i></span></span><br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><br /></span></span>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">4. <a href="https://www.nature.com/articles/gim201766.pdf">Hisado-Oliva A et al</a>. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature.<span class="jrnl" title="Genetics in medicine : official journal of the American College of Medical Genetics">Genet Med</span> 2018;20(1):91-7. </span></span><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><i>Free access.</i></span></span></span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">5. <a href="https://academic.oup.com/jcem/article-pdf/99/4/E713/9050688/jcemE713.pdf">Amano N et al.</a><span class="jrnl" title="The Journal of clinical endocrinology and metabolism"> </span><span class="jrnl" title="The Journal of clinical endocrinology and metabolism">Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. J Clin Endocrinol Metab</span> 2014 Apr;99(4):E713-8. <i>Free access</i>.</span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">6. <a href="https://www.ncbi.nlm.nih.gov/pubmed/24259409">Miura K</a> et al. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A 2014;164A(1):156-63. </span></span><br />
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">7. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25728306">Ko JM</a> et al. Skeletal overgrowth syndrome caused by overexpression of C-type
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">8. <a href="https://www.jstage.jst.go.jp/article/endocrj/57/8/57_K10E-164/_pdf/-char/en">Yasoda A, Nakao K.</a>. Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. Endocr J 2010;57(8):659-66. <i>Free access</i>.</span></span><br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><br />9.<a href="https://www.ncbi.nlm.nih.gov/pubmed/8200946"> Hunt PJ et al</a>. Bioactivity and metabolism of C-type natriuretic peptide in normal man.<span class="ref__series"><i> J Clin Endocrinol Metab</i> <span class="ref__seriesDate">1994; </span><span class="ref__seriesVolume">78</span></span>: <span class="ref__seriesPages">1428-35. </span></span></span><br />
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">11. <a href="http://jpet.aspetjournals.org/content/jpet/353/1/132.full.pdf">Wendt DJ et al</a>.
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represents a new therapeutic approach for treatment of fibroblast growth
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">12. <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1813446">Savarirayan R et al</a>. C-type natriuretic peptide analogue therapy in children with achondroplasia. NEJM June 18, 2019. DOI: 10.1056/NEJMoa1813446. Published ahead of print.<br /> </span></span><br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">13. <a href="https://isds2019.exordo.com/programme/presentation/283">Chan D et al.</a> Pharmacokinetic and exposure-response analysis of vosoritide in children with achondroplasia. Abstract. To be presented at the ISDS 2019 Meeting, Oslo, Norway, Sep 12, 2019. <i>Free access</i>.<br /><br />14.<a href="http://jpet.aspetjournals.org/content/jpet/early/2019/06/24/jpet.119.258251.full.pdf"> Breinholt VA et al.</a> TransCon CNP, a sustained-release C-Type Natriuretic Peptide prodrug, a potentially safe and efficacious new therapeutic modality for the treatment of comorbidities associated with FGFR3-related skeletal dysplasias. J Pharmacol Exp Ther <span class="highwire-cite-metadata-date highwire-cite-metadata">June 24, 2019, </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">jpet.119.258251. </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">Published ahead of print. <i>Free access</i>.</span></span></span><br />
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><i><b>16.</b></i><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680#pone-0212680-g007"> </a><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680#pone-0212680-g007">Morozumi N et al</a>. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism.<span class="jrnl" title="PloS one"> PLoS One</span> 2019 Feb 22;14(2):e0212680. <i>Free access.</i></span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><br />18. <a href="https://www.nature.com/articles/s41598-017-07044-8.pdf">Matsushita M</a>. Clinical
dosage of meclozine promotes longitudinal bone growth, bone volume, and
trabecular bone quality in transgenic mice with achondroplasia. <span class="jrnl" title="Scientific reports">Sci Rep</span> 2017;7(1):7371<span class="jrnl" title="Scientific reports"></span>. <i>Free access</i>.</span></span><br />
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">19. <a href="https://www.jci.org/articles/view/83926/pdf">Komla-Ebri D et al</a>. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model.<span class="jrnl" title="The Journal of clinical investigation"> J Clin Invest</span> 2016;126(5):1871-84. <i>Free access</i>.</span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">20. <a href="https://www.jci.org/articles/view/94912/pdf">Kanai Y et al</a>. Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance.<span class="jrnl" title="The Journal of clinical investigation"> J Clin Invest</span> 2017;127(11):4136-47. <i>Free access</i>.</span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">21. <a href="https://www.ncbi.nlm.nih.gov/pubmed/25231866">Yamashita A et al</a>. Statin treatment rescues FGFR3 skeletal dysplasia phenotypes.<span class="jrnl" title="Nature"> Nature</span> 2014; 513(7519):507-11.</span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">22. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201492">Holmes G et al</a>. C-type natriuretic peptide analog treatment of craniosynostosis in a Crouzon syndrome mouse model. <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=natriuretic+peptdie+crouzon+syndrome#">PLoS One.</a> 2018;13(7):e0201492. <i>Free access</i>.</span></span><br />
<br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">23.<a href="https://academic.oup.com/hmg/article-pdf/27/13/2276/25061148/ddy133.pdf">Tajan M et al</a>. Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth. Hum Mol Genet 2018;27(13):2276-89. <i> Free access</i>.</span></span><br />
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">24. <a href="https://www.ncbi.nlm.nih.gov/pubmed/30239744">Inoue SI et al</a>. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.<span class="jrnl" title="Human molecular genetics"> Hum Mol Genet</span> 2019; 28(1):74-83.</span></span></div>
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<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">25. <a href="https://www.ebiomedicine.com/article/S2352-3964(19)30010-6/pdf">Zheng C et al</a>. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 2019;40:695-709. <i>Free access</i>.</span></span><br />
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif"><br /></span></span>
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">26. <a href="https://www.ncbi.nlm.nih.gov/books/NBK1152/">Pauli RM, Legare JM</a>. Achondroplasia. 2018. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. <i>Free access</i>.</span></span><br />
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<div class="desc">
<span style="font-size: small;"><span face=""trebuchet ms" , sans-serif">27. <a href="https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.13542">Fredwall SO et al</a>. Current knowledge of medical complications in adults with achondroplasia: A scoping review.<span class="jrnl" title="Clinical genetics"> Clin Genet</span>. 2019 Mar 27. <i>Free access</i>.</span></span></div>
Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com2tag:blogger.com,1999:blog-4791085249231790709.post-71441527226576666772019-06-11T12:34:00.000-04:002019-06-11T12:34:01.866-04:00Tratando la acondroplasia: efectos del CNP en los huesos craneales y un nuevo análogo.<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="es"><i>Traducción: Google Translator, con revisión del Autor</i></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="es"><i><br /></i></span></span></span>
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span class="tlid-translation translation" lang="es">En el escenario ...<br /><br />Aunque toda nuestra atención está ahora dirigida a los estudios clínicos con vosoritide, TA-46 y el CNP de Ascendis, es bueno tener en cuenta también las investigaciones recientemente publicadas, que pueden traer nuevas terapias para la acondroplasia y otras displasias esqueléticas.<br /><br />... y detrás de las escenas<br /><br />Un nuevo estudio en ratones, publicado por una industria farmacéutica en asociación con el pionero grupo japonés que describió la relevancia del péptido natriurético del tipo C (CNP) en el crecimiento óseo, mostró cómo este péptido fue capaz de rescatar la hipoplasia del tercio medio de la cara y la estenosis del foramen magnum típicas de la acondroplasia (1). En su estudio, administraron uno de los subtipos naturales de CNP a ratones jóvenes por infusión subcutánea continua por cuatro semanas y verificaron que no sólo hubo un aumento significativo en el crecimiento de los huesos largos, pero también en los huesos craneales, incluyendo los del tercio medio de la cara y la base del cráneo, donde se encuentra el foramen magnum (Figura 1) (1).<br /><br /><br />Figura 1. Efectos del CNP-53 en el peso corporal, longitud, morfología craneofacial y tamaño del foramen magnum en ratas CNP-KO.<br /><br /> </span></span></span><br />
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<span style="font-size: small;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgmxi9lCR5AgEMLKRv_18pzqWLsXNIIH6b_5ilN9iMMz5IvdWFJgGl71ZmkVoLF3cywrhjx8KRruNnRnaUjbHgCOqsyDdBO0de050IxIzCv_SW2vGgJyceneVAn1ZlAHdZe9ieqeQi9UuQ/s1600/journal.pone.0216340.g004.PNG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1600" data-original-width="1092" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgmxi9lCR5AgEMLKRv_18pzqWLsXNIIH6b_5ilN9iMMz5IvdWFJgGl71ZmkVoLF3cywrhjx8KRruNnRnaUjbHgCOqsyDdBO0de050IxIzCv_SW2vGgJyceneVAn1ZlAHdZe9ieqeQi9UuQ/s640/journal.pone.0216340.g004.PNG" width="436" /></a></span></div>
<span style="font-size: small;"><br /><span style="font-size: x-small;">(A) Peso corporal y longitud, (B) longitudes relativas de la morfología craneofacial para ratones WT, (C) tamaño relativo del foramen magnum para ratones WT. WT, WT ratones que recibieron vehículo; CNP-KO, ratones CNP-KO que recibieron vehículo; Ratas CNP-KO + CNP, CNP-KO que recibieron CNP-53 (aproximadamente 0,5 mg / kg / día). Los datos se expresan como los promedios ± DP de 4-5 ratas.<br />*, P <0,05, **, P <0,01 vs. ratas WT o CNP-KO usando la prueba t de Student.<br />De PLoS One (acceso libre), reproducido aquí sólo con fines educativos y disponible en: https://doi.org/10.1371/journal.pone.0216340.g004.</span><br /><br /><br /><span style="font-family: "Trebuchet MS", sans-serif;">Estos son hallazgos interesantes, ya que nos llevan a plantear cuestiones en torno a evidencias anteriores, que mostraron que las terapias potenciales para la acondroplasia pueden no funcionar en los huesos craneales, especialmente en los niños mayores. En el estudio de Matsushita et al. (2) descubrieron que el FGFR3 mutante promovió el cierre prematuro de sincrondoses y la fusión de centros de osificación de los huesos craneales ya con 10 días de vida en un modelo de acondroplasia en ratones y argumentaran que cualquier intervención terapéutica potencial debería comenzar antes de ese cierre. En el estudio que estamos revisando aquí, sin embargo, los ratones iniciaron la infusión de CNP en la quinta semana de vida, tarde, considerando que el principal período de crecimiento en ratas y ratones abarca las ocho primeras semanas de vida.<br /><br />El crecimiento ocurre en ratas y ratones a un ritmo mucho más acelerado que en los humanos (4), por lo que, aunque presentan patrones de desarrollo muy similares, los hallazgos en los estudios con estos animales deben interpretarse con cierta cautela.<br /><br />Un punto a considerar es que el grupo japonés utilizó una infusión subcutánea continua de CNP en su estudio. La infusión continua de CNP puede ejercer efectos más intensos sobre los huesos, como ya vimos en estudios anteriores publicados por el mismo grupo, como aquel en que ellos crearon un modelo de ratón con acondroplasia, pero también con sobre-expresión del gen CNP (con superproducción del CNP ). Los altos niveles de CNP en ese modelo causaron sobrecrecimiento de los animales, una cierta sorpresa, ya que tenían acondroplasia, también (3, echar un vistazo a las imágenes del artículo).<br /><br />En la acondroplasia, una de las principales complicaciones comúnmente observadas al inicio de la vida es exactamente la estenosis del foramen magnum, la cual puede requerir intervención quirúrgica. Podemos inferir que tales anormalidades craneales están presentes en el nacimiento. Con base en las evidencias proporcionadas por los estudios arriba mencionados y otros, se puede concluir que cualquier terapia debe ser iniciada lo antes posible, con el objetivo de prevenir o reducir las complicaciones neurológicas. Sin embargo, si los resultados presentados por Yotsumoto et al. (1) reflejan un beneficio potencial incluso en los animales más viejos, entonces es razonable pensar que los tratamientos administrados a niños de mayor edad todavía puede ser beneficioso en el contexto de los huesos del cráneo.<br /><br />También es posible que presentaciones de liberación sostenida de CNP, tales como el TransCon CNP de la Ascendis y el compuesto ASB20123, una nueva molécula constituida de un fragmento activo del CNP y de un fragmento de la hormona grelina que está bajo desarrollo por la Daiichi Sankio (5), pueden tener efectos más potentes y / o más fuertes que los análogos del CNP con una vida media más corta, como el vosoritide (BMN-111). De hecho, datos divulgados por Ascendis en 2017 en un congreso científico mostraron que su versión del CNP era más potente que el vosoritide (6).<br /></span></span><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span class="tlid-translation translation" lang="es"><span class="" title="">Y finalmente, como algunos de los autores del artículo brevemente revisado aquí trabajan hoy para la Daiichi Sankio, no sería una sorpresa para mí que el campo de desarrollo clínico de la acondroplasia pueda ver a otro jugador entrando en la competición en breve.</span> <span class="" title="">Y ellos ya están buscando indicaciones terapéuticas adicionales para su molécula (7).</span></span></span></span><br />
<br />
<br />
<i><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span class="tlid-translation translation" lang="es"><span class="" title="">Referencias</span></span></span></span></i><br />
<br />
<span class="tlid-translation translation" lang="es"><span class="" title=""><span style="font-size: small;"><span style="font-family: "Trebuchet MS", sans-serif;"><span>1. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216340">Yotsumoto T et al</a>.
Foramen magnum stenosis and midface hypoplasia in C-type natriuretic
peptide deficient rats and restoration by the administration of human
C-type natriuretic peptide with 53 amino acids. PLoS ONE 2019; 14(5):
e0216340. <i>Acesso libre</i>.<br /> <br />2.<a href="https://academic.oup.com/hmg/article/18/2/227/2527065"> Matsushita T et al.</a>
FGFR3 promotes synchondrosis closure and fusion of ossification centers
through the MAPK pathway. Hum Mol Gen 2009;18(2):227–40. </span><span><span><i>Acesso libre</i></span>.<br /> <br /> 3. <a href="https://academic.oup.com/endo/article/150/7/3138/2456109">Yasoda A et al.</a>
Systemic administration of C-type natriuretic peptide as a novel
therapeutic strategy for skeletal dysplasias. Endocrinology.
2009;150(7):3138-44. </span><span><span><i>Acesso libre</i></span>.<br /> <br /> 4. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733029/">Sengupta P</a>. The laboratory rat: relating its age with human's. Int J Prev Med. 2013 Jun; 4(6): 624–630. </span><span><span><i>Acesso libre</i></span>. <br /> <br /> 5. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680">Morozumi N et al.</a>
ASB20123: A novel C-type natriuretic peptide derivative for treatment
of growth failure and dwarfism. PLoS One 2019; 14(2):e0212680. </span><span><span><i>Acesso libre.</i></span></span><br />
<span><span><i> </i></span> <br />
6. Breinholt VM et al.TransCon CNP, a Sustained-Release Prodrug of
C-Type Natriuretic Peptide, Effects Positive Bone Growth in Young
Cynomolgus Monkeys and in a Mouse Model of Achondroplasia. Poster
presented at the Endocrine Society (ENDO) Annual Meeting and Expo, April
1-4, 2017 (Orlando, FL). Endocrin Rev 2017; 38 (3 Suppl).<br /> <br /> 7.<a href="https://academic.oup.com/hmg/article/28/1/74/5099468"> Inoue SI et al</a>.
C-type natriuretic peptide improves growth retardation in a mouse model
of cardio-facio-cutaneous syndrome.Hum Mol Genet 2019;28(1):74-83.</span></span></span> </span></span><br />
<span class="tlid-translation translation" lang="es"><span class="" title=""> </span></span>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-71046767906535585652019-06-06T09:45:00.000-04:002019-06-11T12:38:32.322-04:00Tratando a acondroplasia: efeitos do CNP nos ossos cranianos e um novo análogo.<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><b><i>No palco...</i></b><br /><br />Embora toda a nossa atenção esteja agora dirigida aos estudos clínicos com vosoritide, TA-46 e o CNP da Ascendis, é bom ficar de olho também nas pesquisas recentemente publicadas, as quais podem trazer novas terapias para a acondroplasia e outras displasias esqueléticas.<br /><br /><b><i>... e nos bastidores</i></b><br /><br />Um novo estudo em ratos, publicado por uma indústria farmacêutica em associação com o </span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">pioneiro </span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">grupo japonês que descreveu a relevância do peptídeo natriurético do tipo C (CNP) no crescimento ósseo, mostrou como este peptídeo foi capaz de resgatar a hipoplasia do terço médio da face e a estenose do foramen magnum típicas da acondroplasia (1). Em seu estudo, eles administraram um dos subtipos naturais de CNP a ratos jovens por infusão subcutânea contínua por quatro semanas e verificaram que não apenas houve um aumento significativo no crescimento dos ossos longos, mas também nos ossos cranianos, incluindo os </span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">do terço médio da face</span></span></span> e da base do crânio, onde o foramen magnum está localizado (Figura 1) (1).<br /><br /><br />Figura 1. Efeitos do CNP-53 no peso corporal, comprimento, morfologia craniofacial e tamanho do foramen magnum em ratos CNP-KO.</span></span></span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg7MVUZtZ0MhtS0QmcgeROYVv5tycEJgYTSHvFG6QHIx52gBAgGILOaoCrE827yfjAroAnA_wtkvox4W2Rp-NSZTGtVfClm3YcBzxVGisFuT0vAop52g2O62oFR_yvhXz8Ng0eiZPixb3w/s1600/journal.pone.0216340.g004.PNG" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1600" data-original-width="1092" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg7MVUZtZ0MhtS0QmcgeROYVv5tycEJgYTSHvFG6QHIx52gBAgGILOaoCrE827yfjAroAnA_wtkvox4W2Rp-NSZTGtVfClm3YcBzxVGisFuT0vAop52g2O62oFR_yvhXz8Ng0eiZPixb3w/s640/journal.pone.0216340.g004.PNG" width="435" /></a></div>
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"> </span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><br /><span style="font-size: x-small;">(A) Peso corporal e comprimento, (B) comprimentos relativos da morfologia craniofacial para ratos WT, (C) tamanho relativo do foramen magnum para ratos WT. WT, WT ratos que receberam veículo; CNP-KO, ratos CNP-KO que receberam veículo; Ratos CNP-KO + CNP, CNP-KO que receberam CNP-53 (cerca de 0,5 mg / kg / dia). Os dados são expressos como as médias ± DP de 4-5 ratos.</span></span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span style="font-size: x-small;">*, P <0,05, **, P <0,01 vs. ratos WT ou CNP-KO usando o teste t de Student.<br /><b>De PLoS One (acesso livre), reproduzido aqui apenas para fins educacionais e disponível em: https://doi.org/10.1371/journal.pone.0216340.g004.</b></span></span></span></span><br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span style="font-size: x-small;"><b> </b></span><br /><br />Esses são achados interessantes, uma vez que nos levam a colocar questões em torno de evidências anteriores, que mostraram que terapias potenciais para a acondroplasia podem não funcionar nos ossos cranianos, especialmente em crianças mais velhas. No estudo de Matsushita et al. (2) eles descobriram que o FGFR3 mutante promoveu o fechamento prematuro de sincrondoses e fusão de centros de ossificação dos ossos cranianos já com 10 dias de vida em um modelo de acondroplasia em camundongos e argumentaram que qualquer intervenção terapêutica potencial deveria começar antes desse fechamento. No estudo que estamos revendo aqui, no entanto, os ratos iniciaram a infusão de CNP na quinta semana de vida, tarde, considerando que o principal período de crescimento em ratos e camundongos abrange as oito primeiras semanas de vida.<br /><br />O crescimento ocorre em ratos e camundongos em um ritmo muito mais acelerado do que em humanos (4), portanto, embora apresentem padrões de desenvolvimento muito semelhantes, os achados nos estudos com esses animais devem ser interpretados com certa cautela.<br /><br />Um ponto a considerar é que o grupo japonês utilizou uma infusão subcutânea contínua de CNP em seu estudo. A infusão contínua de CNP pode exercer efeitos mais intensos sobre os ossos, como já vimos em estudos anteriores publicados pelo mesmo grupo, como aquele em que eles criaram um modelo de camundongo com acondroplasia, mas também com superexpressão do gene CNP (com superprodução do CNP). Os altos níveis de CNP nesse modelo causaram supercrescimento dos animais, uma certa surpresa, já que tinham acondroplasia, também (3; dê uma olhada nas imagens do artigo).<br /><br />Na acondroplasia, uma das principais complicações comumente observadas no início da vida é exatamente a estenose do foramen magnum, a qual pode exigir intervenção cirúrgica. Podemos inferir que tais anormalidades cranianas estão presentes logo no nascimento. Com base nas evidências fornecidas pelos estudos acima mencionados e outros, pode-se concluir que qualquer terapia deve ser iniciada o mais cedo possível, com o objetivo de prevenir ou reduzir as complicações neurológicas. No entanto, se os resultados apresentados por Yotsumoto et al. (1) refletem um benefício potencial mesmo em animais mais velhos, então é razoável pensar que as terapias dadas a crianças mais velhas ainda podem ser benéficas no contexto dos ossos cranianos.<br /><br />Também é possível que apresentações de liberação sustentada de CNP, tais como o </span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span class="tlid-translation translation" lang="pt">TransCon CNP</span></span></span> da Ascendis e o composto ASB20123, uma molécula constituída de um fragmento ativo do CNP e de um fragmento do hormônio grelina, que está sob desenvolvimento pela Daiichi Sankio (5), podem ter efeitos mais potentes e/ou mais fortes do que os análogos do CNP com uma meia-vida mais curta, como o vosoritide (BMN-111). De fato, dados divulgados pela Ascendis em 2017 em um congresso científico mostraram que sua versão do CNP era mais potente que o vosoritide (6).<br /><br />E finalmente, como alguns dos autores do artigo brevemente revisto aqui trabalham hoje para a Daiichi Sankio, não seria uma surpresa para mim que o campo de desenvolvimento clínico da acondroplasia possa ver mais um jogador entrando na competição em breve. E eles já estão procurando por indicações terapêuticas adicionais para sua molécula (7).<br /><br /><br /><i><b>Referências</b></i></span></span></span><br />
<br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">1. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216340">Yotsumoto T et al</a>. Foramen magnum stenosis and midface hypoplasia in C-type natriuretic peptide deficient rats and restoration by the administration of human C-type natriuretic peptide with 53 amino acids. PLoS ONE 2019; 14(5): e0216340. <i>Acesso livre</i>.<br /> <br />2.<a href="https://academic.oup.com/hmg/article/18/2/227/2527065"> Matsushita T et al.</a> FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Gen 2009;18(2):227–40. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i>Acesso livre</i></span></span>.<br /> <br /> 3. <a href="https://academic.oup.com/endo/article/150/7/3138/2456109">Yasoda A et al.</a> Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology. 2009;150(7):3138-44. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i>Acesso livre</i></span></span>.<br /> <br /> 4. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733029/">Sengupta P</a>. The laboratory rat: relating its age with human's. Int J Prev Med. 2013 Jun; 4(6): 624–630. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i>Acesso livre</i></span></span>. <br /> <br /> 5. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680">Morozumi N et al.</a> ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoS One 2019; 14(2):e0212680. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i>Acesso livre.</i></span></span></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i> </i></span></span> <br /> 6. Breinholt VM et al.TransCon CNP, a Sustained-Release Prodrug of C-Type Natriuretic Peptide, Effects Positive Bone Growth in Young Cynomolgus Monkeys and in a Mouse Model of Achondroplasia. Poster presented at the Endocrine Society (ENDO) Annual Meeting and Expo, April 1-4, 2017 (Orlando, FL). Endocrin Rev 2017; 38 (3 Suppl).<br /> <br /> 7.<a href="https://academic.oup.com/hmg/article/28/1/74/5099468"> Inoue SI et al</a>. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.Hum Mol Genet 2019;28(1):74-83.<br /><br /> <br /><br /> </span></span>Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-74133901380363963492019-06-05T15:02:00.002-04:002019-06-11T08:54:05.566-04:00Treating Achondroplasia: CNP effects on cranial bones and a new analogue. <span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i><b>The spotlight...</b></i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">While all our attention is now directed to the clinical trials with vosoritide, TA-46 and Ascendis' CNP, it is good to keep also an eye on the recently published research that may bring new therapies for achondroplasia and other skeletal dysplasias.</span></span><br />
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<i><b><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">... and the backstage</span></span></b></i><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">A new study in rats, published by </span></span><span style="font-family: "trebuchet ms" , sans-serif;">a pharma industry in association with </span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">the pioneer Japanese group</span></span><span style="font-family: "trebuchet ms" , sans-serif;"> who described the relevance of C-type natriuretic peptide (CNP) in bone growth, shows how this peptide was capable of rescuing the characteristic <i>midface hypoplasia</i> and <i>foramen magnum stenosis</i> seen in achondroplasia (1). In their study, they administered one of the natural subtypes of CNP to young rats via a continuous subcutaneous infusion for four weeks and found out that not only there was a significant increase in long bone growth but also in cranial bones, including those of the midface and the skull base, where the foramen magnum is located (Figure 1)(1). </span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">Figure 1. <span style="font-size: small;">Effects of CNP-53 on body weight, length, craniofacial morphology, and foramen magnum size in CNP-KO rats.</span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><img alt="Fig 4" class="figure-img" height="640" src="https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0216340.g004&type=large" width="435" /></span>
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<span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;">(A)
Body weight and length, (B) relative lengths of craniofacial morphology
to WT rats, (C) relative size of foramen magnum to WT rats. WT, WT rats
which received vehicle; CNP-KO, CNP-KO rats which received vehicle;
CNP-KO + CNP, CNP-KO rats which received CNP-53 (ca. 0.5 mg/kg/day).
Data are expressed as the means ± SD of 4–5 rats. *, <i>P</i> < 0.05, **, <i>P</i> < 0.01 vs. WT or CNP-KO rats using Student’s <i>t</i>-test.</span></span></div>
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<b><span style="font-size: x-small;"><span style="font-family: "trebuchet ms" , sans-serif;">From PLoS One (open access), reproduced here for educational purposes only and available at: <a href="https://doi.org/10.1371/journal.pone.0216340.g004">https://doi.org/10.1371/journal.pone.0216340.g004.</a></span></span></b>
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<span style="font-family: "trebuchet ms" , sans-serif;">These are interesting findings since they lead us to pose questions around previous evidence showing that potential therapies for achondroplasia might not work in cranial bones, specially if given in older children. In the study by Matsushita et al. (2) they found that the mutant FGFR3 promoted premature closure of synchondroses and fusion of ossification centers of the cranial bones </span><span style="font-family: "trebuchet ms" , sans-serif;">as early as 10 days of life </span><span style="font-family: "trebuchet ms" , sans-serif;">in a mouse model of achondroplasia, and argued that any potential therapeutic intervention should start before that closure. </span><span style="font-family: "trebuchet ms" , sans-serif;">In the study we are reviewing here however, rats started CNP infusion in the fifth week of life,
late considering that their main growth period encompasses their first eight
weeks of life.</span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">Development
occurs in rats and mice in a much more accelerated pace than in humans
(4) so, although they present very similar development patterns, findings
in studies in these animals must be interpreted with some caution.</span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">One point to consider is that the Japanese group used a continuous subcutaneous infusion of CNP in their study. Continuous infusion of CNP may exert more intensive effects on bones as we have already seen in previous studies published by the same group, such as the one in which they created a mouse model with achondroplasia but also with overexpression of the CNP gene (with super production of CNP). The high CNP levels in that model caused animal overgrowth, which was kind of a surprise as they had achondroplasia (3; take a look on their pictures). </span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">In achondroplasia, one of the main complications commonly seen early in life is exactly the foramen magnum stenosis, which may require surgical intervention, and we can infer that such cranial abnormalities are present right at birth. Based in evidence provided by the above mentioned studies and others one can conclude that any therapy must be started as early as possible with the goal of preventing or reducing </span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-family: "trebuchet ms" , sans-serif;">neurological </span>complications. Nevertheless, if the results presented by Yotsumoto et al. (1) reflect a potential benefit even in older animals, then it is reasonable to think that therapies given to older children may still be beneficial in the context of the cranial bones.</span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">It is also possible that sustained release presentations of CNP, such as the one in development by Ascendis (<a href="https://ascendispharma.com/product-pipeline/publications/#transcon-cnp">TransCon CNP</a>) and the recently disclosed molecule ASB20123, constituted by a fusion of an active fragment of CNP and a backbone part of the hormone <i>ghrelin</i> that is under development by Daiichi Sankio (5), may have more potent and/or stronger effects than CNP analogues with a shorter half life such as vosoritide. In fact, data released by Ascendis in a scientific meeting showed that their version of CNP was more potent than vosoritide (6).</span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">And finally, as some of the authors of the article briefly reviewed here today work for Daiichi Sankio, it would not be a surprise for me that the achondroplasia clinical development landscape may see an additional player coming onboard soon. And they are already looking for additional therapeutic indications for their molecule (7).</span><br />
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<i><b><span style="font-family: "trebuchet ms" , sans-serif;">References</span></b></i><br />
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<span style="font-family: "trebuchet ms" , sans-serif;">1. <span style="font-size: small;"><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216340">Yotsumoto T et al</a>. Foramen magnum stenosis and midface hypoplasia in C-type natriuretic peptide deficient rats and restoration by the administration of human C-type natriuretic peptide with 53 amino acids.</span> PLoS ONE 2019; 14(5): e0216340. <span style="font-size: small;"><i>Free access.</i></span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br />2.<a href="https://academic.oup.com/hmg/article/18/2/227/2527065"> Matsushita T et al.</a> FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Gen 2009;18(2):227–40. <i>Free access.</i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">3. <a href="https://academic.oup.com/endo/article/150/7/3138/2456109">Yasoda A et al.</a> Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology. 2009;150(7):3138-44. <i>Free access.</i></span></span><br />
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<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">4. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733029/">Sengupta P</a>. The laboratory rat: relating its age with human's. Int J Prev Med. 2013 Jun; 4(6): 624–630. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><i>Free access. </i></span></span></span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"> </span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">5. <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212680">Morozumi N et al.</a> ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoS One 2019; 14(2):e0212680.</span></span><br />
<br />
<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">6. Breinholt VM et al.<span class="no-download">TransCon CNP, a
Sustained-Release Prodrug of C-Type Natriuretic Peptide, Effects
Positive Bone Growth in Young Cynomolgus Monkeys and in a Mouse Model of
Achondroplasia. </span>Poster presented at the Endocrine Society (ENDO) Annual
Meeting and Expo, April 1-4, 2017 (Orlando, FL). </span><span style="font-family: "trebuchet ms" , sans-serif;">Endocrin Rev 2017; 38 (3 Suppl).</span></span><br />
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<span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;">7.<a href="https://academic.oup.com/hmg/article/28/1/74/5099468"> Inoue SI et al</a>. </span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.</span></span><span style="font-size: small;"><span style="font-family: "trebuchet ms" , sans-serif;"></span></span><span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Hum Mol Genet 2019;28(1):74-83.</span></span><br />
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<br />Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0tag:blogger.com,1999:blog-4791085249231790709.post-84292000315965754012019-03-20T17:51:00.003-04:002019-07-08T21:20:59.855-04:00Therachon e Ascendis estão recrutando participantes para seus estudos de história natural<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;"><br />Novidade<br /><br />Tanto a Therachon quanto a Ascendis Pharma publicaram novas informações sobre seus estudos no site ClinicalTrials.gov.<br /><br />A Ascendis Pharma já iniciou seu estudo de história natural nos EUA, Canadá, Reino Unido, Alemanha e Austrália. Confira <a href="https://www.clinicaltrials.gov/ct2/show/NCT03875534?term=achondroplasia&draw=1&rank=1">aqui</a>. Por enquanto, há apenas um centro recrutando, mas a situação pode mudar rapidamente e esses registros não são atualizados em tempo real.<br /><br />Infelizmente, o registro do estudo não divulga informações de contato dos centros de pesquisa. Embora não seja difícil adivinhar quem são os investigadores e seus centros, as pessoas interessadas podem entrar em contato diretamente com a <a href="https://ascendispharma.com/about-us/contact/">Ascendis </a>para obter mais informações.<br /><br />A Therachon também está recrutando participantes para seu estudo de história natural. Seu registro é mais completo, divulgando os hospitais onde os centros estão localizados. Você pode verificar a lista <a href="https://www.clinicaltrials.gov/ct2/show/NCT03794609?term=achondroplasia&rank=4">aqui</a>.<br /><br />O que é um estudo de história natural?<br /><br />O estudo de história natural é um estudo observacional para rastrear os padrões de crescimento dos participantes. O objetivo é comparar esses padrões com o crescimento observado após o início da terapia. Como ainda existem informações escassas sobre os padrões de crescimento na acondroplasia em crianças, esses estudos de história natural provavelmente seriam uma tentativa de preencher essa lacuna de informação e tentar detectar mudanças nos padrões de crescimento após a intervenção farmacológica.<br /> </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Os desenvolvedores do vosoritide também conduziram um <a href="https://www.clinicaltrials.gov/ct2/show/NCT01603095?term=achondroplasia&draw=1&rank=7">estudo de história natural</a> antes do início do estudo da fase 2. No entanto, é interessante notar que, independentemente das diferenças observadas nos padrões de crescimento no seu <a href="http://www.ashg.org/2016meeting/pdf/ASHG2016-posterabstracts.pdf">estudo de fase 2</a> (ver página 1301, resumo # 2347W), eles ainda foram requisitados a usar um estudo duplo-cego padrão, controlado por placebo no estudo de fase 3 que está em andamento. Em outras palavras, as diferenças no crescimento observadas após a intervenção do medicamento, quando comparadas com antes da terapia seriam aceitas como prova de conceito (a droga funciona), mas não como um parâmetro de eficácia válido para levar à aprovação da medicação. Nesse sentido, apenas um estudo controlado por placebo confirmaria que o medicamento estaria realmente funcionando. <br /> </span></span><br />
<span style="font-family: "trebuchet ms" , sans-serif;"><span style="font-size: small;">Como já expressei no passado, penso que essa abordagem é aquém da ideal em condições como a acondroplasia, onde qualquer terapia farmacológica só pode ser bem sucedida por um tempo limitado.<br /><br />Afinal, crescimento tem data de vencimento.</span></span><br />
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Morrys C. Kaisermannhttp://www.blogger.com/profile/08589139743362708286noreply@blogger.com0