Work Package 4: Impact of brain dystrophins restoration on dystrophic mice phenotype

Led by Aurelie Goyenvalle (UVSQ)

Work Package 4 aims at assessing the impact that postnatal restoration of dystrophin expression has on neurocognitive / behavioural features in the different DMD mouse models using genetic tools. Mouse models lacking multiple dystrophin isoforms such as the mdx52 were found to present more severe behavioural deficits than mouse models lacking full-length dystrophin alone (WP3 results). To elucidate whether these deficits could be rescued, WP4 partners aimed at postnatally restoring expression of dystrophin in the brain using locally administered exon skipping tools in the mdx52 mouse model. Different genetic tools were available in the consortium members’ laboratories and have therefore been compared to determine optimal restoration of dystrophin after their intracerebral administration.  

This comparison revealed that the bilateral ICV injection of tcDNA induced the highest level of exon 51 skipping in the brain of mdx52 mice compared to other types of antisense oligonucleotides and this resulted in Dp427 protein restoration. These findings were summarized in a multi-partner manuscript that has been published in March 2023 in the journal Cells. This also represented the first milestone of WP4 which was the determination of the optimal genetic tool allowing restoration of dystrophin expression in the brain of dystrophic mice. 

Using these optimal conditions, WP4 then demonstrated that partial restoration of Dp427 was associated with improvements in emotional deficits, including anxiety, stress reactivity and fear learning deficits. These findings suggest that restoring dystrophin in the brain using antisense oligonucleotides may have potential therapeutic effects on emotional deficits in DMD, highlighting a novel approach for treating the behavioural disturbances in this disease. These findings were published in March 2023 in Molecular Therapy Nucleic acids. 

Further work from WP4 currently aims at investigating the additional rescue of the Dp140 isoform in the brain of dystrophic mice and its impact on behavioural outcomes.