This proposal deals with new therapeutic approaches for a rare, disabling genetic skin disease, dystrophic epidermolysis bullosa (DEB). The hallmark of DEB is skin blistering induced by minor friction, followed by chronic wounds and severe scarring that progresses into generalized soft tissue fibrosis. Among the many symptoms, joint contractures and mitten deformities of hands and feet cause severe disability, and the fibrosis of the dermis increases tissue stiffness and favours development of squamous cell carcinoma, an often lethal complication of the disease. Thus far, gene-, cell- and protein-based therapy approaches for DEB have shown some promise in preclinical tests, but little benefit in pilot clinical trials. Therefore, alternative approaches to improve the health and quality of life of patients are needed. - Here, we will assess the potential of repurposing drugs and other biomolecules to prevent the progression of soft tissue fibrosis in DEB. The approach is based on findings that TGF-ß and JAK/STAT-mediated signalling is causally involved in DEB fibrosis. We will elucidate the molecular and cellular mechanisms of these signalling pathways in DEB and use FDA/EMA-approved TGF-ß and JAK/STAT-antagonists and other biomolecules, to interfere with signalling in murine and human DEB cells in vitro and to attenuate soft tissue fibrosis in DEB mouse models in vivo. The data will deliver important information on the mode of action of TGF-ß antagonists in DEB, and lay a basis for pharmacological intervention to inhibit severe complications in this intractable disease.