Therapy for ectopic calcification in pseudoxanthoma elasticum abstract pseudoxanthoma elasticum (PXE) is a rare monogenic disease that leads to ectopic calcification of the eyes, skin, and vasculature

PXE results from loss-of-function mutations in the ABCC6 gene. Normally, ABCC6 transports ATP from the liver into circulation where IT is then converted into adenosine monophosphate (AMP) and inorganic pyrophosphate (PPI) by the enzyme ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). PPI in circulation is a potent inhibitor of ectopic calcification; IT antagonizes the ability of inorganic phosphate to crystallize with calcium to form hydroxyapatite. Patients with PXE have a 70% reduction of normal circulating levels of PPI which results in late-onset generalized systemic calcification. PPI replacement therapy has been challenging given the short half-life and misconceived notion that IT could not be delivered orally. Recently, we have developed a proprietary gastric-release salt form of PPI for oral administration that achieves clinically meaningful increases in circulating PPI in mice and in humans. Orally delivered PPI in ABCC6-/- mice attenuates calcification and establishes proof-of-concept. In this phase 1 project, we will conduct pharmacokinetic and toxicology studies and then evaluate LYS-PPI in an animal model of PXE. Phase 2 work will comprise IND-enabling studies, culminating in the filing of an IND. A successful outcome of this work will provide a proprietary mechanism-based first-in-class therapy for PXE and other disorders of abnormal ectopic calcification.