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

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 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 transcript and protein level. 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.