INZ ‐701 prevents ectopic tissue calcification and restores bone architecture and growth in ENPP1 deficient mice

AbstractEctonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular ATP to generate pyrophosphate (PPi), an inorganic metabolite with potent anti ‐calcification 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 Hypophosphatemi c 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 inEnpp1asj/asj mice, a murine model of ENPP1 deficiency.Enpp1asj/asj mice have undetectable plasma PPi, lower plasma phosphate and higher FGF23 levels compared to WT mice.Enpp1asj/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.Enpp1asj/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...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research