Combination S100A1 and ARC gene therapy as a treatment for Duchenne muscular dystrophy cardiomyopathy.

Duchenne muscular dystrophy (DMD) is a lethal pediatric striated muscle disease caused by loss of dystrophin for which there is no cure. Cardiomyopathy is the leading cause of death among individuals with DMD, and effective therapeutics to treat DMD cardiomyopathy are a major unmet clinical need. This work investigated adeno-associated viral (AAV) gene therapy approaches to treat DMD cardiomyopathy by overexpression of the calcium binding proteins S100A1 and apoptosis repressor with caspase recruitment domain (ARC). Using the severe D2.mdx mouse model of DMD, we identified that S100A1 gene therapy improves the diastolic dysfunction associated with DMD cardiomyopathy, whereas ARC gene therapy prolongs survival. The combination of S100A1 and ARC in a single bicistronic vector improves the long-term cardiac outcome and histopathology of D2.mdx mice and the development of heart failure caused by micro-dystrophin expression, and its safety was exhibited via intracoronary delivery in a canine model of DMD. In addition to robust cardiac benefits, S100A1-ARC gene therapy benefits D2.mdx skeletal muscle function and histopathology when driven by a striated muscle promoter. Together, these findings indicate that S100A1-ARC gene therapy represents an effective treatment for DMD cardiomyopathy and may have therapeutic benefits in treating other forms of cardiomyopathy and muscle pathologies.