ArticleMolecular therapy. Methods & clinical development2016
100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy.
Article in Molecular therapy. Methods & clinical development, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- 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
- Genetic strategies for therapy of Duchenne muscular dystrophy.Molecular therapy. Nucleic acids · 2025Review
- Long-Term Dystrophin Replacement Therapy in Duchenne Muscular Dystrophy Causes Cardiac Inflammation.JACC. Basic to translational science · 2025Article
- Unleashing the potential of mRNA therapeutics for inherited neurological diseases.Brain : a journal of neurology · 2024Review
- Potential limitations of microdystrophin gene therapy for Duchenne muscular dystrophy.JCI insight · 2024Article
- The Implication of Hinge 1 and Hinge 4 in Micro-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy.Human gene therapy · 2023Article
- Sustainable recovery of MBNL activity in autoregulatory feedback loop in myotonic dystrophy.Molecular therapy. Nucleic acids · 2022Article
- The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy.Human molecular genetics · 2019Article
- Cardiac-Specific Expression of ΔH2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy.Human gene therapy · 2018Article
- A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy.Molecular therapy. Methods & clinical development · 2017Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index) became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity.
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Registered trials
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