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Updated: Jan 7, 2026
Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
Published on: May 24, 2016
Behavioral improvement in dystrophic mdx23 mouse following repeated antisense oligonucleotides injections
Artadokht Aghaeipour1,2, Manuela Mitsogiannis3, Claire Fergus4
1The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, WC1N 1EH London, UK.
Abstract:
Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the DMD gene that disrupt the production of functional dystrophin proteins. Intellectual disability and neurobehavioral complications including autism spectrum disorder, attention-deficit disorders, and anxiety cumulatively occur in 33%-43% of the patients due to deficiency of multiple dystrophin isoforms produced in brain. Previous work also identified behavioral abnormalities in the mdx23 mouse model of DMD. In this work we mapped the expression of the different dystrophin isoforms in different areas of the mouse brain. Next, we determined the behavioral phenotypes that best differentiate mdx23 (lacking the Dp427 isoform) and wild-type mice. Finally, we investigated the response to intracisternal magna (ICM) injection of exon-skipping phosphorodiamidate morpholino oligomer (PMO) antisense oligonucleotides, which induces skipping of exon 23 and restores the reading frame on these phenotypes. PMO administration led to low, detectable, restoration of dystrophin protein and DMD exon skipping in different brain regions. Treated mdx23 male mice exhibited a small but significant rescue of their enhanced fear response. We conclude that ICM delivery of PMO leads to low levels of dystrophin restoration, but these levels are sufficient to elicit a modest behavioral phenotype in mdx23 mice.
Insights
Duchenne muscular dystrophy (DMD) treatment using antisense oligonucleotides showed modest behavioral improvements in mice. Intracisternal magna delivery of PMO restored some dystrophin protein, rescuing fear responses in the mdx23 mouse model.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Duchenne muscular dystrophy (DMD) is a genetic disorder caused by DMD gene mutations, leading to dystrophin deficiency.
- DMD patients exhibit neurobehavioral issues, including intellectual disability and autism spectrum disorder, linked to brain dystrophin isoform deficits.
- The mdx23 mouse model displays behavioral abnormalities relevant to DMD.
Purpose of the Study:
- To map dystrophin isoform expression in the mouse brain.
- To identify behavioral phenotypes differentiating mdx23 and wild-type mice.
- To assess the efficacy of exon-skipping PMO treatment delivered via ICM for behavioral rescue in mdx23 mice.
Main Methods:
- Mapping dystrophin isoform expression across mouse brain regions.
- Behavioral phenotyping of mdx23 and wild-type mice.
- Intracisternal magna (ICM) administration of exon 23-skipping PMO in mdx23 mice, followed by dystrophin assessment and behavioral testing.
Main Results:
- PMO administration resulted in detectable dystrophin restoration and DMD exon skipping in various brain regions.
- Treated mdx23 male mice showed a statistically significant reduction in their exaggerated fear response.
- Low-level dystrophin restoration was sufficient to elicit a modest behavioral rescue.
Conclusions:
- ICM delivery of PMO can achieve low-level dystrophin restoration in the brain.
- This level of restoration is adequate for a modest rescue of specific behavioral phenotypes in the mdx23 mouse model.
- Further research may explore optimizing delivery and dosage for more substantial therapeutic effects.
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