Ectopic calcification represents a pathologic process characterized by mineralization of soft tissues.
Pseudoxanthoma Elasticum (PXE) is an autosomal recessive genetic disorder characterized by progressive
ectopic calcification of the eyes, skin heart and blood vessels and associated with devastating clinical sequelae
such as blindness, sudden death and skin problems such as poor wound healing. PXE is an orphan disease
and though ABCC6 has been identified as the causative gene, there currently do not exist any therapies for
PXE. In this application we identify a novel molecular target, ENPP1 (ectonucleotide-pyrophosphatase 1) as a
critical mediator of calcification in PXE. We demonstrate that ENPP1 is dramatically upregulated in calcific
tissues in PXE and alters the pyrophosphate/phosphate balance to create a permissive environment for
calcification to occur. We have created small molecules and monoclonal antibodies targeting ENPP1 and
demonstrate the role of these agents in preventing calcification in PXE. Using murine models of PXE along
with human pluripotent stem cell modeling of PXE, we investigate the molecular and biochemical role of
ENPP1-PPi-Pi axis in mediating calcification in PXE and identify novel pharmacologic agents for the treatment
of this incurable disorder. If successful, our proposal may lead directly to the identification of novel therapeutic
strategies for PXE.