title: 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.
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.) dwendt@bmrn.com.
authors: Daniel J
authors: DJ
authors: Wendt
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Melita
authors: M
authors: Dvorak-Ewell
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Sherry
authors: S
authors: Bullens
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Florence
authors: F
authors: Lorget
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Sean M
authors: SM
authors: Bell
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Jeff
authors: J
authors: Peng
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Sianna
authors: S
authors: Castillo
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Mika
authors: M
authors: Aoyagi-Scharber
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Charles A
authors: CA
authors: O'Neill
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Pavel
authors: P
authors: Krejci
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: William R
authors: WR
authors: Wilcox
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: David L
authors: DL
authors: Rimoin
authors: BioMarin Pharmaceutical Inc., Novato, California (D.J.W., M.D.-E., Sh.B., F.L., S.M.B., J.P., S.C., M.A.-S., C.A.O., St.B.); and Cedars-Sinai Medical Center, Los Angeles, California (P.K., W.R.W., D.L.R.).
authors: Stuart
authors: S
authors: Bunting
mesh_terms: D000130:Achondroplasia / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D020098:Natriuretic Peptide, C-Type / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015260:Neprilysin / Q000378:metabolism*; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D020098:Natriuretic Peptide, C-Type; C000632572:vosoritide; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D015260:Neprilysin