ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy

Ronald A Albright; Paul Stabach; Wenxiang Cao; Dillon Kavanagh; Isabelle Mullen; Alexander A Braddock; Mariel S Covo; Martin Tehan; Guangxiao Yang; Zhiliang Cheng; Keith Bouchard; Zhao-Xue Yu; Stephanie Thorn; Xiangning Wang; Ewa J Folta-Stogniew; Alejandro Negrete; Albert J Sinusas; Joseph Shiloach; George Zubal; Joseph A Madri; Enrique M De La Cruz; Demetrios T Braddock

doi:10.1038/ncomms10006

ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy

Nat Commun. 2015 Dec 1:6:10006. doi: 10.1038/ncomms10006.

Authors

Ronald A Albright¹, Paul Stabach¹, Wenxiang Cao², Dillon Kavanagh¹, Isabelle Mullen¹, Alexander A Braddock¹, Mariel S Covo¹, Martin Tehan¹, Guangxiao Yang¹, Zhiliang Cheng³, Keith Bouchard³, Zhao-Xue Yu³, Stephanie Thorn⁴, Xiangning Wang⁴, Ewa J Folta-Stogniew⁵, Alejandro Negrete⁶, Albert J Sinusas⁴, Joseph Shiloach⁶, George Zubal⁷, Joseph A Madri¹, Enrique M De La Cruz², Demetrios T Braddock¹

Affiliations

¹ Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
² Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
³ Alexion, Cheshire, Connecticut 06410, USA.
⁴ Department of Medicine and Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
⁵ WM Keck Biotechnology Research Laboratory, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
⁶ Biotechnology Core Laboratory, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
⁷ Z-Concepts LLC, East Haven, Connecticut 06512, USA.

Abstract

Diseases of ectopic calcification of the vascular wall range from lethal orphan diseases such as generalized arterial calcification of infancy (GACI), to common diseases such as hardening of the arteries associated with aging and calciphylaxis of chronic kidney disease (CKD). GACI is a lethal orphan disease in which infants calcify the internal elastic lamina of their medium and large arteries and expire of cardiac failure as neonates, while calciphylaxis of CKD is a ubiquitous vascular calcification in patients with renal failure. Both disorders are characterized by vascular Mönckeburg's sclerosis accompanied by decreased concentrations of plasma inorganic pyrophosphate (PPi). Here we demonstrate that subcutaneous administration of an ENPP1-Fc fusion protein prevents the mortality, vascular calcifications and sequela of disease in animal models of GACI, and is accompanied by a complete clinical and biomarker response. Our findings have implications for the treatment of rare and common diseases of ectopic vascular calcification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arteries / enzymology
Arteries / pathology
Disease Models, Animal
Female
Humans
Immunoglobulin Fc Fragments / administration & dosage
Immunoglobulin Fc Fragments / genetics
Immunoglobulin Fc Fragments / metabolism
Immunoglobulin G / genetics
Immunoglobulin G / metabolism
Infant, Newborn
Infant, Newborn, Diseases / enzymology*
Infant, Newborn, Diseases / genetics
Infant, Newborn, Diseases / mortality
Infant, Newborn, Diseases / prevention & control*
Male
Mice, Inbred C57BL
Phosphoric Diester Hydrolases / administration & dosage
Phosphoric Diester Hydrolases / genetics
Phosphoric Diester Hydrolases / metabolism*
Pyrophosphatases / administration & dosage
Pyrophosphatases / genetics
Pyrophosphatases / metabolism*
Vascular Calcification / enzymology*
Vascular Calcification / genetics
Vascular Calcification / mortality
Vascular Calcification / prevention & control*

Substances

Immunoglobulin Fc Fragments
Immunoglobulin G
Phosphoric Diester Hydrolases
ectonucleotide pyrophosphatase phosphodiesterase 1
Pyrophosphatases

Supplementary concepts

Arterial calcification of infancy