A phytic acid derivative INS-3001 prevents ectopic mineralization in an Abcc6(-/-) mouse model of pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders, affects the skin, eyes and the cardiovascular system. PXE is caused by biallelic inactivating mutations in the ABCC6 gene encoding a putative efflux transporter ABCC6. There is no effective treatment for the systemic manifestations of PXE. In this study, the efficacy of INS-3001, a derivative of Myo-inositol hexakisphosphate (phytic acid), was tested for prevention of ectopic mineralization in the Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 6 weeks of age, the time of onset of ectopic mineralization, were treated with INS-3001 at 4, 20 and 100 mg/kg/day administered by subcutaneous implantation of Alzet pumps. As a positive control, a group of mice was treated with etidronate (0.78 mg/kg/day), a bisphosphonate previously shown by us to prevent ectopic mineralization, and untreated Abcc6-/- mice served as a reference group. Mice were necropsied at 12 weeks of age and the degree of mineralization was analyzed in the muzzle skin containing vibrissae, a biomarker of the mineralization process in these mice. Histologic examination revealed extensive mineralization in the muzzle skin of untreated mice, while little, if any, mineralization was present in mice treated with INS-3001, similar to etidronate treated mice. Quantitative calcium assay demonstrated that the amount of calcium in the muzzle skin biopsies from the INS-3001 treated Abcc6-/- mice was similar to that of wild type mice devoid of ectopic mineralization, indicating that INS-3001 was highly efficient in preventing deposition of calcium hydroxyapatite complexes. These results suggest that INS-3001 might provide a promising treatment strategy for PXE, and could be applicable to other ectopic mineralization disorders. Future studies are in progress to investigate whether lower doses of INS-3001 and intermittent administration would have similar therapeutic effects on ectopic mineralization.