A phytic acid analogue INS-3001 prevents ectopic calcification in an Abcc6-/- mouse model of pseudoxanthoma elasticum.

Abstract

Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic calcification disorders, affects the skin, eyes and the cardiovascular system due to inactivating mutations in the ABCC6 gene. There is no effective treatment for the systemic manifestations of PXE. In this study, the efficacy of INS-3001, an analogue of phytic acid, was tested for inhibition of ectopic calcification in an Abcc6-/- mouse model of PXE. In prevention study, Abcc6-/- mice, at 6weeks of age, the time of onset of ectopic calcification, were treated with INS-3001 with 0.16, 0.8, 4, 20 or 100mg/kg/day administered by subcutaneous implantation of osmotic pumps, as well as 4mg/kg/day by subcutaneous injection thrice weekly or 14, 4 and 0.8mg/kg/day once weekly subcutaneous injection. Mice were necropsied at 12weeks of age. Histologic examination and quantitative calcium assay revealed that mice receiving 6weeks of continuous INS-3001 administration via osmotic pumps showed dose-dependent inhibition of muzzle skin calcification with complete response at 4mg/kg/day and a minimum effective dose at 0.8mg/kg/day. INS-3001 plasma concentrations were dose-dependent and largely consistent during treatment for each dose. thrice weekly and once weekly subcutaneous injections of INS-3001 also prevented calcification. In established disease study, 12-week-old Abcc6-/- mice with extensive calcification were continuously administered INS-3001 at 4mg/kg/day for a follow-up of 12weeks. INS-3001 treatment was found to stabilize existing calcification that had developed at start of treatment. These results suggest that INS-3001 may provide a promising preventive treatment strategy for PXE, a currently intractable ectopic calcification disorder.