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.

Public Health Relevance

Pseudoxanthoma Elasticum is an autosomal recessive genetic disorder characterized by progressive calcification of multiple organs. The causative gene has been identified but mechanisms of calcification remain unclear and therapies elusive. In this proposal, we identify a critical molecular pathway mediating calcification and target this pathway to delineate novel strategies for treating PXE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR075867-01A1
Application #
9884160
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Park, Heiyoung
Project Start
2020-02-01
Project End
2023-11-30
Budget Start
2020-02-01
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095