Wednesday, June 5, 2019

Treating Achondroplasia: CNP effects on cranial bones and a new analogue.

The spotlight...

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.

... and the backstage

A new study in rats, published by a pharma industry in association with the pioneer Japanese group who described the relevance of C-type natriuretic peptide (CNP) in bone growth, shows how this peptide was capable of rescuing the characteristic midface hypoplasia and foramen magnum stenosis 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).


Figure 1. Effects of CNP-53 on body weight, length, craniofacial morphology, and foramen magnum size in CNP-KO rats.






Fig 4


(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. *, P < 0.05, **, P < 0.01 vs. WT or CNP-KO rats using Student’s t-test.
From PLoS One (open access), reproduced here for educational purposes only and available at: https://doi.org/10.1371/journal.pone.0216340.g004.

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 as early as 10 days of life in a mouse model of achondroplasia, and argued that any potential therapeutic intervention should start before that closure. 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.

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.
 
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). 

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 neurological 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.

It is also possible that sustained release presentations of CNP, such as the one in development by Ascendis (TransCon CNP) and the recently disclosed molecule ASB20123, constituted by a fusion of an active fragment of CNP and a backbone part of the hormone ghrelin 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).

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).

 
References

1. Yotsumoto T et al. 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. Free access.

2. Matsushita T et al. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Gen 2009;18(2):227–40. Free access.


3. Yasoda A et al. Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology. 2009;150(7):3138-44. Free access.

4. Sengupta P. The laboratory rat: relating its age with human's. Int J Prev Med. 2013 Jun; 4(6): 624–630. Free access.  

5. Morozumi N et al. ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism. PLoS One 2019; 14(2):e0212680.

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).

7. Inoue SI et al. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.Hum Mol Genet 2019;28(1):74-83.








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