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 6 weeks of age, the time of onset of ectopic calcification, were treated with INS‐3001 with 0.16, 0.8, 4, 20 or 100 mg/kg/day administered by subcutaneous implantation of osmotic pumps, as well as 4 mg/kg/day by subcutaneous injection thrice weekly or 14, 4 and 0.8 mg/kg/day once weekly subcutaneous injection. Mice were necropsied at 12 weeks of age. Histologic examination and quantitative calcium assay revealed that mice receiving 6 weeks of continuous INS‐3001 administration via osmotic pumps showed dose‐dependent inhibition of muzzle skin calcification with complete response at 4 mg/kg/day and a minimum effective dose at 0.8 mg/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 4 mg/kg/day for a follow‐up of 12 weeks. 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.

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

“…IP6 has poor bioavailability and pharmacokinetics, which has prompted the development of a series of derivatives [ 211 ]. These were tested in Abcc6 −/− mice [ 149 ]. Compound INS-3001 was found to be superior in calcification inhibition both in vitro and in vivo and displayed a better plasma half-life as compared with IP6 [ 211 ].…”

Progress on Biomimetic Mineralization and Materials for Hard Tissue Regeneration

“…When it occurs in joints, heart valves, and blood vessels, it may lead to very serious clinical consequences. Current research on ectopic calcification focuses on the development of effective mineralization inhibitors and mechanisms for inhibiting mineralization in vivo; e.g., Jacobs et al 85 found that INS-3001 (a phytic acid analogue) stabilized calcification that had already appeared at the start of treatment in the Abcc6/mouse PXE model; Barinda et al 86 found that macrophages highly expressed the enzyme carbonic anhydrase 2 (CA2), which played a key role in decalcification of ectopic calcification. In addition, metabolic bone diseases such as chondromalacia and bone Paget's disease are mostly treated with biologic factors in combination with other physical therapy methods.…”

Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

“…Therefore, Schantl et al generated the inositol phosphate analog (OEG2)2-IP4, with more favorable pharmacokinetics and an extended half -life, which is distributed in the US as INS-3001 [ 214 ]. INS-3001 was administered subcutaneously to ABCC6 −/− mice, either continuously via subcutaneous implanted osmotic pumps, or via thrice or once weekly subcutaneous injection [ 216 ]. At a dosage of 4 mg/kg/day of INS-3001, by either continuous or cyclical administration, ectopic calcification was prevented or preserved.…”