Informace o publikaci

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

Autoři	WENDT Daniel J. DVORAK-EWELL Melita BULLENS Sherry LORGET Florence BELL Sean M. PENG Jeff CASTILLO Sianna AOYAGI-SCHARBER Mika O'NEILL Charles A. KREJČÍ Pavel WILCOX William R. RIMOIN David L. BUNTING Stuart
Rok publikování	2015
Druh	Článek v odborném periodiku
Časopis / Zdroj	Journal of Pharmacology and Experimental Therapeutics
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
Doi	http://dx.doi.org/10.1124/jpet.114.218560
Obor	Farmakologie a lékárnická chemie
Klíčová slova	ENDOCHONDRAL OSSIFICATION; SKELETAL DYSPLASIAS; 24.11 ENKEPHALINASE; CYCLASE-B; IN-VIVO; ACHONDROPLASIA; CHONDROCYTES; OVEREXPRESSION; METABOLISM; HYDROLYSIS
Popis	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.