INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice.

Autor: Cheng Z; Inozyme Pharma, Boston, MA, USA., O'Brien K; Inozyme Pharma, Boston, MA, USA., Howe J; Inozyme Pharma, Boston, MA, USA., Sullivan C; Inozyme Pharma, Boston, MA, USA., Schrier D; Inozyme Pharma, Boston, MA, USA., Lynch A; Inozyme Pharma, Boston, MA, USA., Jungles S; Inozyme Pharma, Boston, MA, USA., Sabbagh Y; Inozyme Pharma, Boston, MA, USA., Thompson D; Inozyme Pharma, Boston, MA, USA.
Jazyk: angličtina
Zdroj: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2021 Aug; Vol. 36 (8), pp. 1594-1604. Date of Electronic Publication: 2021 May 05.
DOI: 10.1002/jbmr.4315
Abstrakt: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss-of-function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ-701, a human ENPP1-Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ-701 were investigated in Enpp1 asj/asj mice, a murine model of ENPP1 deficiency. Enpp1 asj/asj mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild-type (WT) mice. Enpp1 asj/asj mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1 asj/asj mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ-701. Treatment of ENPP1-deficient mice every other day with INZ-701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1 asj/asj mice, demonstrating the potential of INZ-701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR).
(© 2021 American Society for Bone and Mineral Research (ASBMR).)
Databáze: MEDLINE
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