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Combination S100A1 and ARC gene therapy as a treatment for Duchenne muscular dystrophy cardiomyopathy
David W Hammers1,2, Cora C Hart1,2, Eli A Zerpa1,2
1Department of Pharmacology & Therapeutics and.
Insights
Gene therapy using S100A1 and ARC shows promise for Duchenne muscular dystrophy (DMD) cardiomyopathy. This approach improves cardiac function and survival in mouse models, offering hope for treating this lethal pediatric muscle disease.
Area of Science:
- Cardiovascular Biology
- Gene Therapy
- Muscle Diseases
Background:
- Duchenne muscular dystrophy (DMD) is a fatal pediatric condition causing muscle degeneration.
- Cardiomyopathy is the primary cause of death in DMD patients, highlighting an urgent need for effective treatments.
- Current therapeutic options for DMD cardiomyopathy are limited.
Purpose of the Study:
- To investigate adeno-associated viral (AAV) gene therapy for DMD cardiomyopathy.
- To evaluate the efficacy of overexpressing S100A1 and apoptosis repressor with caspase recruitment domains (ARC) in treating DMD.
- To assess the safety and efficacy of a combined S100A1-ARC gene therapy approach.
Main Methods:
- Utilized the severe D2.mdx mouse model of DMD.
- Administered AAV gene therapy vectors encoding S100A1 and/or ARC.
- Assessed cardiac function, survival, and histopathology.
- Evaluated safety in a canine model of DMD via intracoronary delivery.
Main Results:
- S100A1 gene therapy improved diastolic dysfunction in DMD cardiomyopathy.
- ARC gene therapy alone prolonged survival in D2.mdx mice.
- Combined S100A1-ARC gene therapy significantly improved long-term cardiac outcomes and histopathology.
- The combined therapy demonstrated safety in a canine DMD model.
- S100A1-ARC gene therapy also benefited skeletal muscle function and histopathology in D2.mdx mice.
Conclusions:
- S100A1-ARC gene therapy is a promising treatment for DMD cardiomyopathy.
- This therapeutic strategy offers potential benefits for other forms of cardiomyopathy and muscle pathologies.
- The findings support the development of S100A1-ARC gene therapy as a viable treatment for DMD.
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 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.
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