Dual S100A1 and ARC gene therapy as a treatment for DMD cardiomyopathy

Abstract

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 amongst 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 domains (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 both S100A1 and ARC in a single bicistronic vector improves the long-term cardiac outcome of D2.mdx mice, development of heart failure caused by micro-dystrophin expression, and exhibits safety via intracoronary delivery in a canine model of DMD. Furthermore, S100A1-ARC gene therapy provides functional benefits when expressed in D2.mdx skeletal muscle. Together, these findings indicate that S100A1-ARC gene therapy represents an effective treatment for DMD cardiomyopathy and may be effective in treating other forms of cardiomyopathy and muscle pathologies. SIGNIFICANCE STATEMENTCardiomyopathy is the leading cause of death amongst individuals with Duchenne muscular dystrophy (DMD). Effective therapeutics to treat DMD cardiomyopathy represent a major unmet clinical need. This work identifies the dual gene therapy approach of S100A1 and ARC as an effective treatment that improves long-term cardiac function and life-expectancy in severe mouse model of DMD. Intracoronary delivery of this AAV-based gene therapy also exhibits safety and evidence of efficacy in dystrophic canines. Furthermore, functional benefits in skeletal muscle are also incurred via S100A1-ARC expression in striated muscle. These findings indicate that S100A1-ARC therapy is an effective treatment for DMD cardiomyopathy whose benefits may be applicable for other forms of cardiac and muscle disease.