Pharmacologic Intervention for Ectopic Calcification

摘要

ABSTRACT This application revolves around ectopic calcification disorders, pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), two autosomal recessive diseases with considerable morbidity and mortality due to calcium hydroxyapatite deposition in the skin, eyes, and the cardiovascular system. There is currently no effective or specific treatment for the ectopic calcification in these disorders. We have developed and characterized mouse models for both PXE and GACI, and these mice now form the platform for preclinical development of therapeutic strategies for these two, currently intractable conditions. The unifying pathological finding in these ectopic calcification disorders is reduced plasma inorganic pyrophosphate (PPi) levels. While significant insight was gained in these disorders, disease mechanism-directed treatment by targeting PPi deficiency prevented new calcification but failed to remove existing ectopic calcification. In this proposal, we will test the overall hypothesis that counteracting ectopic calcification, either by prevention of mineral deposition in the fetus and/or removal of the existing deposits postnatally, will provide treatment approaches with clinical stabilization or cure for patients with PXE or GACI. The therapeutic drug, acetazolamide, has the great potential of counteracting ectopic calcification, primarily due to its physicochemical and cellular mechanisms which are independent of plasma PPi levels. We will specifically focus on two areas of investigation: (a) Prevention of prenatal arterial calcification in GACI by administration of acetazolamide to the mothers during pregnancy, with or without continued treatment of the newborns; this drug will be repurposed from its previous applications to treat various calcification disorders; and (b) We will further focus our efforts to remove existing calcification in PXE and GACI by administration of acetazolamide. These studies will utilize combined prevention and removal approaches to counteract ectopic calcification, providing scientific premise to the investigation. Collectively, our proposed studies will provide critical translational information from preclinical approaches that will allow development of novel treatment for currently intractable disorders PXE and GACI. We also expect that our findings will advance clinical management of ectopic calcification in general, potentially applicable to a number of other diseases, both genetic and acquired.