title: Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia.
abstract: 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 (FGFR3). C-type natriuretic peptide (CNP) antagonizes FGFR3 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 Fgfr3(Y367C/+) mice and showed the presence of ACH-related clinical features in this mouse model. We found that in Fgfr3(Y367C/+) 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.
authors.affiliation: BioMarin Pharmaceutical, Novato, CA 94949, USA.
authors.forename: Florence
authors.initials: F
authors.lastname: Lorget
authors.forename: Nabil
authors.initials: N
authors.lastname: Kaci
authors.forename: Jeff
authors.initials: J
authors.lastname: Peng
authors.forename: Catherine
authors.initials: C
authors.lastname: Benoist-Lasselin
authors.forename: Emilie
authors.initials: E
authors.lastname: Mugniery
authors.forename: Todd
authors.initials: T
authors.lastname: Oppeneer
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Wendt
authors.forename: Sean M
authors.initials: SM
authors.lastname: Bell
authors.forename: Sherry
authors.initials: S
authors.lastname: Bullens
authors.forename: Stuart
authors.initials: S
authors.lastname: Bunting
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Tsuruda
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
authors.forename: Federico
authors.initials: F
authors.lastname: Di Rocco
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D000130:Achondroplasia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006132:Growth Plate / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051379:Mice; D009154:Mutation; D020098:Natriuretic Peptide, C-Type / Q000031:analogs & derivatives* / Q000737:chemistry / Q000502:physiology / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012886:Skull / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D020098:Natriuretic Peptide, C-Type; C000632572:vosoritide; D051498:Receptor, Fibroblast Growth Factor, Type 3