title: ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Albright
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Stabach
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Dillon
authors.initials: D
authors.lastname: Kavanagh
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mullen
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Braddock
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Mariel S
authors.initials: MS
authors.lastname: Covo
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Tehan
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Guangxiao
authors.initials: G
authors.lastname: Yang
authors.affiliation: Alexion, Cheshire, Connecticut 06410, USA.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Alexion, Cheshire, Connecticut 06410, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Bouchard
authors.affiliation: Alexion, Cheshire, Connecticut 06410, USA.
authors.forename: Zhao-Xue
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: Department of Medicine and Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thorn
authors.affiliation: Department of Medicine and Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Wang
authors.affiliation: WM Keck Biotechnology Research Laboratory, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Ewa J
authors.initials: EJ
authors.lastname: Folta-Stogniew
authors.affiliation: Biotechnology Core Laboratory, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Negrete
authors.affiliation: Department of Medicine and Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Sinusas
authors.affiliation: Biotechnology Core Laboratory, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shiloach
authors.affiliation: Z-Concepts LLC, East Haven, Connecticut 06512, USA.
authors.forename: George
authors.initials: G
authors.lastname: Zubal
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: De La Cruz
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Demetrios T
authors.initials: DT
authors.lastname: Braddock
mesh_terms: D000818:Animals; D001158:Arteries / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D010727:Phosphoric Diester Hydrolases / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D061205:Vascular Calcification / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*
chemical_list: D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases