486 Systemic collagen VII protein therapy for treatment of advanced RDEB

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin blistering disease associated with progressive multi-organ fibrosis. RDEB is caused by biallelic COL7A1 mutations leading to reduced production or functionality of the extracellular matrix protein, collagen VII (C7), which is necessary for epidermal-dermal adherence. C7 is not simply a structural protein but also has multiple functions, including regulation of TGFβ bioavailability and the inhibition of skin scarring after wounding. The multi-organ involvement of RDEB calls for systemic treatment. Intriguingly, intravenous (IV) administration of recombinant C7 (rC7) improves the clinical phenotype of newborn C7 deficient mice and rescues them from neonatal lethality. The effect on established RDEB in adult animals has not been determined. Here, we used small and large adult RDEB animal models to investigate the disease-modulating abilities of rC7 on established RDEB. In adult RDEB mice, IV-injected rC7 accumulated dose-dependently at the dermal-epidermal junction of wounded skin and oral mucosa. Bi-weekly IV injections of rC7 for 7 weeks in adult RDEB mice reduced new skin blisters and effectively reduced progression of the fibrotic mitten deformities of their paws. The inhibition of fibrosis was mediated through reduction of TGFβ signaling. IV infusion of rC7 in adult dogs with RDEB also improved disease by promoting the healing of blister-induced skin erosions without excessive scarring. In both models, IV C7 was well tolerated. These preclinical studies suggest that repeated IV administration of rC7 is an efficacious systemic treatment for established adult RDEB.