Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism
| Autor: | Florence Lorget, Sean M. Bell, Mika Aoyagi-Scharber, Sianna Castillo, William R. Wilcox, Pavel Krejci, Melita Dvorak-Ewell, David L. Rimoin, Jeff Peng, Charles A. O’Neill, Stuart Bunting, Daniel J. Wendt, Sherry Bullens |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Injections Subcutaneous Dwarfism Blood Pressure Biology Fibroblast growth factor Bone and Bones Achondroplasia Mice Heart Rate Internal medicine medicine Natriuretic peptide Animals Humans Receptor Fibroblast Growth Factor Type 3 Receptor Neprilysin Pharmacology Bone growth Natriuretic Peptide C-Type Fibroblast growth factor receptor 3 medicine.disease Recombinant Proteins Endochondral bone growth Rats Macaca fascicularis Endocrinology NIH 3T3 Cells Molecular Medicine |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 353:132-149 |
| ISSN: | 1521-0103 0022-3565 |
| 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. |
| Databáze: | OpenAIRE |
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