Abstract Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease for which there currently is no cure. RDEB is caused by mutations in the gene encoding type VII collagen (C7), leading to epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wounding and scar formation, and squamous cell carcinoma, the single biggest cause of death in this patient group. The molecular pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB and as such RDEB is a paradigm for understanding the molecular basis of fibrosis. We have shown that RDEB pathogenesis is driven by a radical change in extracellular matrix (ECM) composition and increased TGFβ signaling that is a direct result of C7 loss-of-function in dermal fibroblasts. However, the mechanism of how C7 loss results in extensive fibrosis has until recently remained unclear. Our now published work has identified a direct role for C7 in protein secretion which when defective or absent leads to accumulation of intracellular proteins, and subsequent increases in cellular stress and the initiation of a pro-fibrotic cascade of TGFβ signaling. This paradigm shifting work has shed significant light onto the conundrum in the field presented by RDEB – why does RDEB develop life threatening skin cancers while other forms of Epidermolysis Bullosa (EB), characterized by continued tissue damage and non-healing wounds, do not? In parallel, and using patient cells, we have identified anti-viral drugs, which inhibit the production and release of viral particles (a process known to hijack cellular transport pathways), are normalizing RDEB secretion defects and therefore represent a novel therapeutic approach to treat RDEB by preventing fibrosis. Furthermore, our work comparing RDEB with non-RDEB patient cells has identified increased TGFβ signaling as a potential mechanism of disrupted protein secretion in non-RDEB cells, which is independent of the protein defect in RDEB, and anti-viral drugs may represent a novel anti-fibrotic that could have application to a wider range of diseases, beyond RDEB. Therefore, our proposal seeks to investigate protein secretion defects we have identified in RDEB fibroblasts and determine the mechanism of action of anti- viral drugs in reducing fibrosis. At the same time, we will assess the anti-fibrotic action of anti-viral drugs in a preclinical mouse model of RDEB and if successful future steps (not part of this funding application) will be to initiate a clinical trial of successful candidate drugs. Together, our integrated in vitro and in vivo studies will define and characterize a novel mechanism of progressive fibrosis, and assess preclinical efficacy of new molecular entities that can be translated into the clinic for improved patient treatment.