ArticleSkeletal muscle2024
Golodirsen restores DMD transcript imbalance in Duchenne Muscular Dystrophy patient muscle cells.
Article in Skeletal muscle, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Gene Editing Strategies for Duchenne Muscular Dystrophy: From Molecular Mechanisms to Clinical Translation.Cells · 2026Review
- RNA Therapeutics for Duchenne Muscular Dystrophy: Exon Skipping, RNA Editing, and Translational Insights from Genome-Edited Microminipig Models.International journal of molecular sciences · 2026Review
- Multiplexed Immunophenotyping for Innate Activation Assessment Detects Single-Cell Responses to Immunomodulatory Nucleic Acid Impurities in Therapeutics.The AAPS journal · 2026Article
- Clinical applications of exon-skipping antisense oligonucleotides in neuromuscular diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Valproic Acid Improves Antisense-Mediated Exon-Skipping Efficacy inInternational journal of molecular sciences · 2025Article
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Authors and funding
7 authors.
Funding
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Abstract
backgroundAntisense oligonucleotides (AON) represent a promising treatment for Duchenne muscular dystrophy (DMD) carrying out-of-frame deletions, but also show limitations. In a completed clinical trial golodirsen, approved by FDA to induce skipping of DMD gene exon 53 in eligible patients, we demonstrated increase in DMD expression and protein production, albeit with inter-patient variability.
methodsHere, we investigate further the golodirsen mechanism of action using myotubes derived from MyoD transfected fibroblasts isolated from DMD patients at the baseline of the clinical trial SRP-4053.
resultsWe confirm golodirsen's selectivity and efficiency in removing only exon 53. For the first time in human cells, we revealed a significant reduction in the so called DMD "transcript imbalance", in golodirsen-treated DMD muscle cultures. The transcript imbalance is a unique DMD phenomenon characterized by non-homogeneous transcript expression along its entire length and responsible for the reduced stability of the transcript. Our in-vivo study also showed that the efficiency of exon skipping did not always correspond to a proportional restoration of the dystrophin protein. Predominant nuclear localization of the DMD transcript, observed in patients and animal models, persists even after exon skipping.
conclusionAll these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition.
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