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

Authors

Qirong Mao, Alireza Ahmadi, Sharon de Vries, Laura G M Heezen, Ophélie Vacca, Mathilde Doisy, Annemieke Aartsma-Rus, Maaike van Putten, Aurélie Goyenvalle, Ahmed Mahfouz, Pietro Spitali

Published in

iScience. Volume 29. Issue 8. Pages 116906. Aug 21, 2026. Epub Jul 23, 2026.

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.

PMID:
42542656
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.

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