Key result
Combination S100A1 and ARC gene therapy extends survival ~86% in mice with heart failure.
Why the study?
Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy, and effective therapeutics to treat DMD cardiomyopathy remain a major unmet clinical need.
Does combination S100A1 and ARC gene therapy improve cardiac outcomes and survival in preclinical models of DMD cardiomyopathy?
Does combination S100A1 and ARC gene therapy improve cardiac outcomes and survival in preclinical models of DMD cardiomyopathy?
Combination S100A1 and ARC gene therapy improves cardiac function, histopathology, and survival in preclinical models of DMD cardiomyopathy, representing a potential novel therapeutic approach.
Does not support clinical use of S100A1/ARC gene therapy; leaves open translation from DMD animal models to human trials.
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 and histopathology 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. 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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Hammers et al. (2026) studied Duchenne muscular dystrophy cardiomyopathy. Combination S100A1 and ARC gene therapy vs. Untreated D2.mdx mice and GRMD canines was evaluated on Survival and cardiac function. Combination S100A1 and ARC gene therapy increased mean survival time from 336 days to 625 days in D2.mdx mice with micro-dystrophin associated heart failure and improved long-term cardiac outcomes.
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