AAV-mediated overexpression of wild-type DSG2 as a strategy to contrast Arrhythmogenic (Right Ventricular) Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a dominant, degenerative cardiomyopathy, frequently involved in sudden death of asymptomatic athletes and teenagers. Currently, the main goal of the therapy is the prevention of sudden death occurrence. To this aim, implant of a cardioverter-defibrillator is the most effective strategy, which however should be reserved to selected patients after accurate risk stratification, in view of the high complication rate, costs and significant psychological impact of such therapy, especially in young individuals. Other therapies are palliative and aimed at relieving symptoms and preventing disease progression. Previous and ongoing studies and clinical trials support the safety and applicability of viral vectors, such as AAV, to treat different conditions, including heart disfunctions. The present project aims to test the efficacy of an AAV-based therapeutic approach in preclinical models of ARVC in two complementary platforms, both harboring the same mutation found in an affected patient. We will use 3D in vitro cardiac microtissues, that represent a more mature model than 2D cell cultures, as well as murine models, to assess the efficacy of the treatment in an in vivo context. Overall, expected results have the potential to develop an effective treatment for ARVC and to provide a valuable benefit for affected patients.