ArticleJCI insight2024
Potential limitations of microdystrophin gene therapy for Duchenne muscular dystrophy.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Direct Pharmacological Activation of AMPK Extends Lifespan in Yeast, Worms and Flies.Aging cell · 2026Article
- Functional near-infrared spectroscopy: Systematic mapping of abnormal brain function features in neurological disorders.Neural regeneration research · 2026Article
- Combination S100A1 and ARC gene therapy as a treatment for Duchenne muscular dystrophy cardiomyopathy.JCI insight · 2026Article
- RNA-Based Therapies for Treating Monogenic Cardiomyopathies.The Canadian journal of cardiology · 2026Review
- Adeno-Associated Virus Toxicity in Duchenne Muscular Dystrophy: Mechanisms and Clinical Considerations.Genes · 2026Review
- Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.Skeletal muscle · 2026Article
- Dose- and genotype-dependent cardiac arrhythmia and sudden death in rats following microdystrophin gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Real-world outcomes of delandistrogene moxeparvovec gene therapy: Motor outcomes and emerging safety concerns.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Disease exacerbation in human DMD MYOrganoids enables gene therapy evaluation and unveils persistence of fibrotic activity.NPJ Regenerative medicine · 2026Article
- From molecular correction to functional rescue: delivery, tissue state, and immunobiology as the principal constraints on dystrophin-restoring therapy in Duchenne muscular dystrophy.Frontiers in pharmacology · 2026Review
- Genetic strategies for therapy of Duchenne muscular dystrophy.Molecular therapy. Nucleic acids · 2025Review
- Dystrophin Restorative and Compensatory Gene Addition Therapies for Duchenne Muscular Dystrophy: Could CRISPRa Provide a Realistic Alternative?Muscles (Basel, Switzerland) · 2025Review
- AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects.Gene therapy · 2025Review
- AAV-microutrophin gene therapy confers durable cardioprotection against pharmacologic and exercise-induced injury in the mdx mouse.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.bioRxiv : the preprint server for biology · 2025Article
- A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health.Molecular therapy. Nucleic acids · 2025Article
- Engineering Targeted Gene Delivery Systems for Primary Hereditary Skeletal Myopathies: Current Strategies and Future Perspectives.Biomedicines · 2025Review
- Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice.The Journal of clinical investigation · 2025Article
- Advancing adeno-associated virus for Duchenne muscular dystrophy treatment: Moving beyond rodent models.Molecular therapy. Methods & clinical development · 2025Article
- Long-Term Dystrophin Replacement Therapy in Duchenne Muscular Dystrophy Causes Cardiac Inflammation.JACC. Basic to translational science · 2025Article
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Authors and funding
7 authors.
Funding
Abstract
Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (microdystrophins) are underway for Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with 4 microdystrophin constructs (3 in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using AAV doses comparable with those in clinical trials. We achieved high levels of microdystrophin expression in striated muscles with cardiac expression approximately 10-fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease occurred with 2 of the microdystrophins. The detrimental cardiac effect appears to be caused by variable competition (dependent on microdystrophin design and expression level) between microdystrophin 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-microdystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, these findings suggest that microdystrophin treatments need to avoid excessively high levels of expression in the heart and that cardiac function should be carefully monitored in these patients.
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