2015
Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3-Related Dwarfism
WENDT, Daniel J., Melita DVORAK-EWELL, Sherry BULLENS, Florence LORGET, Sean M. BELL et. al.Základní údaje
Originální název
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. (840 Spojené státy), Melita DVORAK-EWELL (840 Spojené státy), Sherry BULLENS (840 Spojené státy), Florence LORGET (840 Spojené státy), Sean M. BELL (840 Spojené státy), Jeff PENG (840 Spojené státy), Sianna CASTILLO (840 Spojené státy), Mika AOYAGI-SCHARBER (840 Spojené státy), Charles A. O'NEILL (203 Česká republika), Pavel KREJČÍ (203 Česká republika, garant, domácí), William R. WILCOX (840 Spojené státy), David L. RIMOIN (840 Spojené státy) a Stuart BUNTING (840 Spojené státy)
Vydání
Journal of Pharmacology and Experimental Therapeutics, Bethesda, AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2015, 0022-3565
Další údaje
Jazyk
angličtina
Typ výsledku
Článek v odborném periodiku
Obor
30104 Pharmacology and pharmacy
Stát vydavatele
Spojené státy
Utajení
není předmětem státního či obchodního tajemství
Impakt faktor
Impact factor: 3.760
Kód RIV
RIV/00216224:14110/15:00082767
Organizační jednotka
Lékařská fakulta
UT WoS
000351043600015
Klíčová slova anglicky
ENDOCHONDRAL OSSIFICATION; SKELETAL DYSPLASIAS; 24.11 ENKEPHALINASE; CYCLASE-B; IN-VIVO; ACHONDROPLASIA; CHONDROCYTES; OVEREXPRESSION; METABOLISM; HYDROLYSIS
Štítky
Příznaky
Mezinárodní význam, Recenzováno
Změněno: 27. 4. 2015 13:38, Ing. Mgr. Věra Pospíšilíková
Anotace
V originále
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.