Systemic clinical-grade recombinant decorin reduces disease burden and fibrosis in advanced recessive dystrophic epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin and epithelial fragility disease that progresses with severe fibrosis. This fibrosis is debilitating and promotes the development of aggressive squamous cell carcinomas (SCCs). Effective management of fibrosis may improve quality of life in RDEB and reduce the risk of high-risk SCCs. Decorin, a small leucine-rich proteoglycan, has natural fibrosis-limiting activity. Higher expression of decorin has been linked to milder RDEB, and decorin has shown anti-fibrotic effects in multiple models of experimentally induced fibrosis. However, a short circulating half-life, manufacturing challenges, and broad target engagement have limited the development of systemic decorin therapy. Here, we describe scalable production of recombinant human decorin protein core (rh Decorin) and test repeated intravenous administration in a murine model of advanced RDEB. We show that rh Decorin accumulates in the skin and other injured sites and improves RDEB-related signs. Systemic administration enables decorin-mediated direct and indirect inhibition of TGF-β activity in peripheral tissues. Characterization of the dermal collagen matrix revealed evidence of remodeling capacity of fibrotic lesions in RDEB when cellular contractile activities are targeted, providing an explanation for the anti-fibrotic effects of rh Decorin in advanced disease. These results support further evaluation of intravenous rh Decorin for the treatment of RDEB, especially for fibrotic manifestations.