The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy
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Updated: Nov 22, 2025
Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
Published on: May 7, 2020
Dominic Scaglioni1,2, Francesco Catapano1,2,3, Matthew Ellis4,5
1Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK.
Abstract:
During the last decade, multiple clinical trials for Duchenne muscular dystrophy (DMD) have focused on the induction of dystrophin expression using different strategies. Many of these trials have reported a clear increase in dystrophin protein following treatment. However, the low levels of the induced dystrophin protein have raised questions on its functionality. In our present study, using an unbiased, high-throughput digital image analysis platform, we assessed markers of regeneration and levels of dystrophin associated protein via immunofluorescent analysis of whole muscle sections in 25 DMD boys who received 48-weeks treatment with exon 53 skipping morpholino antisense oligonucleotide (PMO) golodirsen. We demonstrate that the de novo dystrophin induced by exon skipping with PMO golodirsen is capable of conferring a histological benefit in treated patients with an increase in dystrophin associated proteins at the dystrophin positive regions of the sarcolemma in post-treatment biopsies. Although 48 weeks treatment with golodirsen did not result in a significant change in the levels of fetal/developmental myosins for the entire cohort, there was a significant negative correlation between the amount of dystrophin and levels of regeneration observed in different biopsy samples. Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human.
Insights
Golodirsen treatment for Duchenne muscular dystrophy (DMD) induced dystrophin protein, which showed functional benefits. This study provides evidence of induced dystrophin
Area of Science:
- Biomedical Science
- Genetics
- Neurology
Background:
- Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration.
- Clinical trials for DMD have focused on inducing dystrophin expression, but its functionality remains questioned due to low levels.
- Exon skipping therapies aim to restore the dystrophin protein in DMD patients.
Purpose of the Study:
- To assess the functionality of de novo dystrophin induced by golodirsen in DMD patients.
- To evaluate histological benefits and markers of regeneration after golodirsen treatment.
- To investigate the correlation between induced dystrophin levels and muscle regeneration.
Main Methods:
- Immunofluorescent analysis of whole muscle sections from 25 DMD boys treated with golodirsen for 48 weeks.
- High-throughput digital image analysis to assess dystrophin-associated proteins and regeneration markers.
- Correlation analysis between dystrophin levels and regeneration markers.
Main Results:
- Golodirsen treatment increased dystrophin-associated proteins in specific sarcolemma regions.
- A significant negative correlation was observed between induced dystrophin levels and muscle regeneration.
- No significant change in fetal/developmental myosins was observed across the cohort.
Conclusions:
- De novo dystrophin induced by exon skipping with golodirsen confers histological benefits in DMD patients.
- The induced dystrophin is functional, as evidenced by increased dystrophin-associated proteins and reduced regeneration.
- This study provides the first evidence of induced dystrophin functionality in human DMD therapeutic interventions.
