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@article{1298520,
author = {Wendt, Daniel J. and DvorakandEwell, Melita and Bullens, Sherry and Lorget, Florence and Bell, Sean M. and Peng, Jeff and Castillo, Sianna and AoyagiandScharber, Mika and O'Neill, Charles A. and Krejčí, Pavel and Wilcox, William R. and Rimoin, David L. and Bunting, Stuart},
article_location = {Bethesda},
article_number = {1},
doi = {http://dx.doi.org/10.1124/jpet.114.218560},
keywords = {ENDOCHONDRAL OSSIFICATION; SKELETAL DYSPLASIAS; 24.11 ENKEPHALINASE; CYCLASE-B; IN-VIVO; ACHONDROPLASIA; CHONDROCYTES; OVEREXPRESSION; METABOLISM; HYDROLYSIS},
language = {eng},
issn = {0022-3565},
journal = {Journal of Pharmacology and Experimental Therapeutics},
title = {Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3-Related Dwarfism},
volume = {353},
year = {2015}
}
TY - JOUR
ID - 1298520
AU - 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
PY - 2015
TI - Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3-Related Dwarfism
JF - Journal of Pharmacology and Experimental Therapeutics
VL - 353
IS - 1
SP - 132-149
EP - 132-149
PB - AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
SN - 00223565
KW - ENDOCHONDRAL OSSIFICATION
KW - SKELETAL DYSPLASIAS
KW - 24.11 ENKEPHALINASE
KW - CYCLASE-B
KW - IN-VIVO
KW - ACHONDROPLASIA
KW - CHONDROCYTES
KW - OVEREXPRESSION
KW - METABOLISM
KW - HYDROLYSIS
N2 - 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.
ER -
WENDT, Daniel J., Melita DVORAK-EWELL, Sherry BULLENS, Florence LORGET, Sean M. BELL, Jeff PENG, Sianna CASTILLO, Mika AOYAGI-SCHARBER, Charles A. O'NEILL, Pavel KREJČÍ, William R. WILCOX, David L. RIMOIN a Stuart BUNTING. Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3-Related Dwarfism. \textit{Journal of Pharmacology and Experimental Therapeutics}. Bethesda: AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2015, roč.~353, č.~1, s.~132-149. ISSN~0022-3565. Dostupné z: https://dx.doi.org/10.1124/jpet.114.218560.
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