Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder characterized by ectopic calcification of elastic fibers throughout the skin, retina, and arteries. It is caused by pathogenic variants in ABCC6, which encodes a transmembrane transporter that primarily localizes to hepatocytes. Loss of ABCC6 function in hepatocytes leads to systemic deficiency of inorganic pyrophosphate (PPi), a potent inhibitor of calcification; such depletion of PPi from the circulation is responsible for multisystemic ectopic calcification seen in PXE. Therefore, liver-targeted variant correction by genome editing and subsequent restoration of systemic PPi may offer a one-and-done therapeutic approach for PXE. The ABCC6 c.3490C>T (p.R1164X) variant is one of the most common variants found in PXE patients. Here, we show that liver-directed correction of the R1164X variant by adenine base editing restores plasma PPi and prevents ectopic skin calcification in mice fed a standard diet or an "acceleration diet" that exacerbates ectopic calcification. These results provide fundamental insight into the molecular etiology of PXE and provide a proof-of-principle that genetic correction of ABCC6 defects through adenine base editing may represent a novel, permanent therapy for the treatment of PXE.