Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.

[achondroplasia]

Achondroplasia (ACH ), the most common form of dwarfism , is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth -factor -receptor 3 (FGFR 3 ). C-type natriuretic peptide (CNP ) antagonizes FGFR 3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK ). Here , we report the pharmacological activity of a 39 amino acid CNP analog (BMN 111 ) with an extended plasma half -life due to its resistance to neutral-endopeptidase (NEP ) digestion . In ACH human growth -plate chondrocytes , we demonstrated a decrease in the phosphorylation of extracellular-signal-regulated kinases 1 and 2 , confirming that this CNP analog inhibits fibroblast-growth -factor -mediated MAPK activation . Concomitantly , we analyzed the phenotype of Fgfr 3 (Y 367 C /+) mice and showed the presence of ACH-related clinical features in this mouse model . We found that in Fgfr 3 (Y 367 C /+) mice , treatment with this CNP analog led to a significant recovery of bone growth . We observed an increase in the axial and appendicular skeleton lengths , and improvements in dwarfism -related clinical features included flattening of the skull , reduced crossbite , straightening of the tibias and femurs , and correction of the growth -plate defect . Thus , our results provide the proof of concept that BMN 111 , a NEP-resistant CNP analog , might benefit individuals with ACH and hypochondroplasia .

Diseases
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Diseases presenting "is an inherited autosomal-dominant chondrodysplasia caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3" symptom

achondroplasia

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