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Evaluating exon skipping in the central nervous system in Duchenne muscular dystrophy using spatial transcriptomics

Journal Article (2026)
Author(s)

Qirong Mao (TU Delft - Electrical Engineering, Mathematics and Computer Science, Leiden University Medical Center)

Alireza Ahmadi (Leiden University Medical Center)

Sharon de Vries (Leiden University Medical Center)

Laura G.M. Heezen (Leiden University Medical Center)

Ophélie Vacca (Université de Versailles St-Quentin)

Mathilde Doisy (Université de Versailles St-Quentin)

Annemieke Aartsma-Rus (Leiden University Medical Center, Duchenne Center Netherlands)

Maaike van Putten (Leiden University Medical Center, Duchenne Center Netherlands)

Ahmed Mahfouz (TU Delft - Electrical Engineering, Mathematics and Computer Science, Leiden University Medical Center)

More Authors (External organisation)

Research Group
Pattern Recognition and Bioinformatics
DOI related publication
https://doi.org/10.1016/j.isci.2026.116906 Final published version
More Info
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Publication Year
2026
Language
English
Research Group
Pattern Recognition and Bioinformatics
Journal title
iScience
Issue number
8
Volume number
29
Article number
116906
Downloads counter
18
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Abstract

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration due to dystrophin deficiency. Dystrophin is also expressed in the brain during development and postnatally, yet a characterization of dystrophin isoform expression across brain cells and regions is lacking, limiting our understanding of the cognitive impairment affecting one-third of the patients and hampering the development of dystrophin-restoring drugs in the central nervous system (CNS). Here, we applied spatial transcriptomics to map Dmd isoforms across mouse brain regions and cell types. Mdx52 mice received exon 51-skipping therapies restoring the Dp427-sized isoform at the transcript and protein levels. We observed distinct spatial patterns: full-length isoforms localized to deeper cortical layers and CA1, while shorter isoforms were enriched in cortical layer 1 and dentate gyrus. We present evidence of isoform restoration, immune activation following treatment, and a framework to evaluate exon-skipping therapies in the CNS using spatial transcriptomics.