Timing matters: exon skipping therapy is most effective when initiated early in a mouse model of Duchenne muscular dystrophy

Stenler, S.; Huang, J.; van Westering, T. L. E.; Coenen-Stass, A. M. L.; Krjutskov, K.; EL Andaloussi, S.; Wood, M. J. A.; Roberts, T. C.

doi:10.64898/2025.12.23.696144

bioRxiv · 10.64898/2025.12.23.696144

Timing matters: exon skipping therapy is most effective when initiated early in a mouse model of Duchenne muscular dystrophy

Stenler, S.·Huang, J.·van Westering, T. L. E.·Coenen-Stass, A. M. L.·Krjutskov, K.·EL Andaloussi, S.·Wood, M. J. A.·Roberts, T. C.

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Abstract

Exon skipping is a leading therapeutic approach for Duchenne muscular dystrophy (DMD), a progressive muscle wasting disorder caused by pathogenic variants in the DMD gene that typically disrupt the translation reading frame. This approach aims to modulate DMD pre-mRNA splicing to re-frame the transcript and generate an internally deleted but partially functional quasi-dystrophin protein. Four exon skipping drugs have received FDA accelerated approval, although their clinical efficacy is very limited. To investigate how treatment timing influences exon skipping outcomes, dystrophin-deficient mdx mice were injected with peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) exon skipping conjugates beginning at either the adult (12-week) or aged (75-week) stages, and tibialis anterior muscles harvested for biochemical and transcriptomic analyses. Mean Dmd exon 23 skipping was 79% in adults and 44% in aged PPMO-treated mdx mice, whereas dystrophin protein restoration was 35% and 8%, respectively. Histopathological improvements were only evident in the adult-treated mice. PPMO-treatment in adult mdx mice induced a broad transcriptomic shift towards a wild-type signature, whereas treatment in aged mice resulted in negligible gene expression changes, indicating that late intervention is ineffective at reversing disease-associated pathologies despite low-level dystrophin restoration. Dystrophin transcript imbalance was corrected only in adult-treated mdx mice. Increased expression of the dystrophin-repressing microRNA miR-31-5p, which was more strongly upregulated in aged mdx muscle, provides a potential mechanistic explanation. In conclusion, PPMO-mediated exon skipping is substantially more effective when initiated in adult rather than aged dystrophic muscle, supporting early therapeutic intervention in DMD-affected individuals.

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Stenler, S., Huang, J., van Westering, T. L. E., Coenen-Stass, A. M. L., Krjutskov, K., EL Andaloussi, S., Wood, M. J. A., Roberts, T. C.. 2025-12-25. Timing matters: exon skipping therapy is most effective when initiated early in a mouse model of Duchenne muscular dystrophy. https://doi.org/10.64898/2025.12.23.696144

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