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.