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Updated: Jun 17, 2026
Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
Published on: May 7, 2020
Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for
Linda J Popplewell1, Carl Adkin, Virginia Arechavala-Gomeza
1School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey TW20 0EX, United Kingdom.
Abstract:
Duchenne muscular dystrophy (DMD) is caused by the lack of functional dystrophin protein, most commonly as a result of a range of out-of-frame mutations in the DMD gene. Modulation of pre-mRNA splicing with antisense oligonucleotides (AOs) to restore the reading frame has been demonstrated in vitro and in vivo, such that truncated but functional dystrophin is expressed. AO-induced skipping of exon 51 of the DMD gene, which could treat 13% of DMD patients, has now progressed to clinical trials. We describe here the methodical, cooperative comparison, in vitro (in DMD cells) and in vivo (in a transgenic mouse expressing human dystrophin), of 24 AOs of the phosphorodiamidate morpholino oligomer (PMO) chemistry designed to target exon 53 of the DMD gene, skipping of which could be potentially applicable to 8% of patients. A number of the PMOs tested should be considered worthy of development for clinical trial.
Insights
Antisense oligonucleotides (AOs) targeting Duchenne muscular dystrophy (DMD) exon 53 show promise for treating patients. This study compared 24 phosphorodiamidate morpholino oligomer (PMO) AOs in vitro and in vivo, identifying candidates for clinical trials.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Duchenne muscular dystrophy (DMD) results from non-functional dystrophin protein due to DMD gene mutations.
- Antisense oligonucleotide (AO) therapy aims to restore dystrophin by modulating pre-mRNA splicing.
- Exon 51 skipping AOs are in clinical trials, offering treatment for 13% of DMD patients.
Purpose of the Study:
- To compare 24 phosphorodiamidate morpholino oligomer (PMO) antisense oligonucleotides (AOs) targeting exon 53 of the DMD gene.
- To evaluate the efficacy of these PMO AOs in vitro using DMD cells and in vivo using a transgenic mouse model.
- To identify promising PMO AOs for potential clinical development to treat DMD.
Main Methods:
- In vitro assessment of 24 PMO AOs in cultured DMD cells.
- In vivo evaluation of PMO AOs in a transgenic mouse model expressing human dystrophin.
- Comparative analysis of AO performance based on exon skipping efficiency and dystrophin restoration.
Main Results:
- Several PMO AOs demonstrated successful exon 53 skipping in DMD cells and the mouse model.
- Restoration of dystrophin expression was observed with effective PMO AOs.
- The study identified multiple PMO candidates with potential for clinical application.
Conclusions:
- The tested PMO AOs targeting DMD exon 53 are effective in restoring the dystrophin reading frame.
- Exon 53 skipping offers a potential therapeutic strategy for approximately 8% of DMD patients.
- Several PMO candidates warrant further development for clinical trials in Duchenne muscular dystrophy treatment.
