Adenovirus-mediated ABCC6 Gene Therapy for Heritable Ectopic Mineralization Disorders.

Loss-of-function mutations in the ABCC6 gene cause pseudoxanthoma elasticum (PXE) and type 2 generalized arterial calcification of infancy (GACI), heritable ectopic mineralization disorders without effective treatment. ABCC6 encodes the putative efflux transporter ABCC6 which is predominantly expressed in the liver. While the substrate of ABCC6 remains unknown, recent studies demonstrated that PXE is a metabolic disorder caused by reduced circulating levels of pyrophosphate (PPi), a potent mineralization inhibitor. Here, we hypothesized that reconstitution of ABCC6 might counteract ectopic mineralization in an Abcc6-/- mouse model of PXE. Intravenous administration of a recombinant adenovirus expressing wild type human ABCC6 in Abcc6-/- mice showed sustained high-level expression of human ABCC6 in the liver for up to 4 weeks, increasing PPi levels in plasma. In addition, adenovirus injection every 4 weeks restored plasma PPi levels, and consequently, significantly reduced ectopic mineralization in the skin of young mice. By contrast, the same treatment in old mice with already established mineral deposits failed to reduce mineralization. These results suggest that adenovirus-mediated ABCC6 gene delivery, when initiated early, is a promising prevention therapy for PXE and GACI, diseases that currently lack preventive or therapeutic options.