Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption

Autor: Rachel Roach, Joseph Sergi, Mark Horn, Mike Favis, Jeanne Sue Magram, Victoria Markiewicz, William B. Snyder, Kymberly Levine, Jennifer Colangelo, Jean Chamoun, Moosa Mohammadi, Jacqueline Vekich, Dikran Aivazian, Edwin Berryman, William J. Reagan, Cedo M. Bagi, Kristen Johnson, Anthony J. Coyle, Brian Robert Miller, Xianjun Cao, Thomas P. Brown
Rok vydání: 2017
Předmět:
Zdroj: Journal of Bone and Mineral Research. 32:2062-2073
ISSN: 0884-0431
DOI: 10.1002/jbmr.3197
Popis: Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/ α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a pre-clinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion and significantly improves bone architecture in the absence of soft tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. This article is protected by copyright. All rights reserved
Databáze: OpenAIRE
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