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.

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

“…Moreover, CNP overexpression in cartilage can prevent the dwarfism that results from the expression of activated Fgfr3 in growth plate chondrocytes, indicating that CNP signaling works antagonistically to Fgfr3 signaling (Yasoda et al, 2004). Remarkably, the systemic administration of either CNP or a CNP pharmacological analog significantly reverses the dwarf phenotype and growth-plate defects in mouse models of achondroplasia (Yasoda et al, 2009;Lorget et al, 2012).…”

Fibroblast growth factor signaling in skeletal development and disease

“…The most promising therapy thus far for treatment of achondroplasia is the use of a stabilized form of CNP called BMN-111 (Lorget et al 2012;Wendt et al 2015). BMN-111 is currently undergoing clinical trials for the treatment of achondroplasia (https://clinicaltrials.gov/ ct2/show/NCT02055157).…”

Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism

“…First, BMN 111, an NEP-resistant CNP variant, is a natural antagonist of the FGFR3 pathway, corrects the phenotype in Fgfr3 ACH/1 mice, and attenuates the phenotype in stronger activating mutations of FGFR3 (TDI; Y367C/1) when given daily subcutaneously (Lorget et al, 2012). Second, CNP and its receptor are expressed in the growth plate.…”

“…), a mutation that results in thanatophoric dysplasia type I (TDI) in humans (Lorget et al, 2012) To test its effectiveness in larger animals, levels that had minimal effects on hemodynamic parameters were chosen and three cohorts of cynomolgus monkeys were dosed. Dosedependent growth was observed in this 6-month study.…”

“…We recently described the pharmacological activity of a 39-amino acid CNP variant (BMN 111; recombinant variant of C-type natriuretic peptide), which has an extended serum halflife due to its resistance to NEP digestion (Lorget et al, 2012). We demonstrated that daily subcutaneous administrations of BMN 111 in an ACH mouse model resulted in increased axial and appendicular skeletal lengths, improvements in dwarfismrelated clinical features including flattening of the skull, straightening of the tibias and femurs, and correction of the growth plate defect.…”