Neonatal Delivery of Exon Skipping Therapeutics Maximizes Brain Dystrophin Rescue in the Mdx52 Mouse Model of Duchenne Muscular Dystrophy
- 1Universite Paris-Saclay, UVSQ, Inserm, IMPROVE, 78000 Versailles, France
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin expression. Beyond progressive muscle degeneration, nearly half of patients exhibit cognitive and behavioral impairments, highlighting the need for effective central nervous system (CNS) therapies. In this study, we investigated whether neonatal delivery could maximize brain dystrophin rescue in mdx52 mice using exon 51 skipping strategies. We compared systemic and intracerebroventricular (ICV) delivery of an antisense oligonucleotide (ASO-51) and an AAV9-mediated U7snRNA approach (scAAV9-U7-Ex51), administered neonatally. Neonatal intravenous ASO-51 induced widespread but transient exon skipping, resulting in limited brain dystrophin restoration. ICV administration markedly increased CNS exon skipping but did not overcome the limited persistence of ASO, leading to progressive loss of exon skipping and dystrophin rescue. In contrast, neonatal ICV delivery of scAAV9-U7-Ex51 achieved robust, widespread, and sustained exon 51 skipping throughout the brain, including the hippocampus, cortex, and cerebellum, resulting in 20-50% restoration of Dp427 expression. These findings demonstrate that early CNS-directed delivery enhances brain dystrophin restoration and establish AAV-U7-mediated exon skipping as a promising strategy for addressing CNS comorbidities in DMD.
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BibTeX
@misc{vacca2026neonatal,
title = {{Neonatal Delivery of Exon Skipping Therapeutics Maximizes Brain Dystrophin Rescue in the Mdx52 Mouse Model of Duchenne Muscular Dystrophy}},
author = {O. VACCA and M. Doisy and C. Nagy and A. Saoudi and X. M. Phongsavanh and O. Le Coz and C. Vaillend and A. Goyenvalle},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.757591},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757591v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Neonatal Delivery of Exon Skipping Therapeutics Maximizes Brain Dystrophin Rescue in the Mdx52 Mouse Model of Duchenne Muscular Dystrophy
AU - O. VACCA
AU - M. Doisy
AU - C. Nagy
AU - A. Saoudi
AU - X. M. Phongsavanh
AU - O. Le Coz
AU - C. Vaillend
AU - A. Goyenvalle
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.757591
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.757591v1
AB - Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin expression. Beyond progressive muscle degeneration, nearly half of patients exhibit cognitive and behavioral impairments, highlighting the need for effective central nervous system (CNS) therapies. In this study, we investigated whether neonatal delivery could maximize brain dystrophin rescue in mdx52 mice using exon 51 skipping strategies. We compared systemic and intracerebroventricular (ICV) delivery of an antisense oligonucleotide (ASO-51) and an AAV9-mediated U7snRNA approach (scAAV9-U7-Ex51), administered neonatally. Neonatal intravenous ASO-51 induced widespread but transient exon skipping, resulting in limited brain dystrophin restoration. ICV administration markedly increased CNS exon skipping but did not overcome the limited persistence of ASO, leading to progressive loss of exon skipping and dystrophin rescue. In contrast, neonatal ICV delivery of scAAV9-U7-Ex51 achieved robust, widespread, and sustained exon 51 skipping throughout the brain, including the hippocampus, cortex, and cerebellum, resulting in 20-50% restoration of Dp427 expression. These findings demonstrate that early CNS-directed delivery enhances brain dystrophin restoration and establish AAV-U7-mediated exon skipping as a promising strategy for addressing CNS comorbidities in DMD.
ER -