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

Abstract

Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH.

Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B

“…Finally, we suggest that understanding the cross-talk between the FGFR3 and GC-B signaling cascades is of increasing medical importance because a protease resistant analog of CNP is in clinical trials as a therapy for increasing longitudinal growth in children with dwarfism [48, 49]. However, a recent report showing higher circulating levels of CNP in children with achondroplasia suggests tissue resistance to CNP [50], which may result from increased dephosphorylation and desensitization of GC-B.…”

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).…”

Skeletal Dysplasias: Growing Therapy for Growing Bones

“…Pharmacologic treatments for ACH are currently in stage 2 clinical trials (Wendt et al, 2015; Klag and Horton, 2016). Treatments are aimed at regulating the function of FGFR3 in growth plate formation (Matsushita et al, 2014).…”

“…FGFR3 negatively regulates bone growth (Faruqi et al, 2014). Its elevated function leads to irregular endochondral ossification (Wendt et al, 2015; Yap and Savarirayan, 2016) and underdeveloped linear bone growth (Liu et al, 2016) resulting from interrupted differentiation of chondrocytes (Yasoda et al, 2009; Wendt et al, 2015; Klag and Horton, 2016). …”