ResearchIn-Press PreviewMuscle biologyTherapeutics Open Access | 10.1172/jci.insight.165869
1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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1Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, United States of America
2Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, United States of America
3Department of Cell Biology, 7 Neurobiology, and Anatomy, Medical College of Wisconsin, Milwakee, United States of America
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Published May 7, 2024 - More info
Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (micro-dystrophins) are underway for individuals with Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with four micro-dystrophin constructs (three in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using doses of AAV comparable to those used in the clinical trials. We achieved high levels of micro-dystrophin expression in striated muscle with cardiac expression ~10 fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of the skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease progression occurred with two of the micro-dystrophins. The detrimental impact on the heart appears to be caused by the high levels of micro-dystrophin resulting in variable competition (dependent on the design of the micro-dystrophin) between micro-dystrophin and utrophin at the cardiomyocyte membrane. There may also be a contribution from an overloading of protein degradation. The significance of these observations for patients currently being treated with AAV-micro-dystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, it suggests that micro-dystrophin treatments need to avoid excessively high levels of expression in the heart and cardiac function should be carefully monitored in these patients.