Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy - CRM - Centre de recherche en myologie - U974 Accéder directement au contenu
Article Dans Une Revue EMBO Molecular Medicine Année : 2024

Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy

Francesco Galli
Maira Rossi
Laura Perani

Résumé

Abstract Cell therapy for muscular dystrophy has met with limited success, mainly due to the poor engraftment of donor cells, especially in fibrotic muscle at an advanced stage of the disease. We developed a cell-mediated exon skipping that exploits the multinucleated nature of myofibers to achieve cross-correction of resident, dystrophic nuclei by the U7 small nuclear RNA engineered to skip exon 51 of the dystrophin gene. We observed that co-culture of genetically corrected human DMD myogenic cells (but not of WT cells) with their dystrophic counterparts at a ratio of either 1:10 or 1:30 leads to dystrophin production at a level several folds higher than what predicted by simple dilution. This is due to diffusion of U7 snRNA to neighbouring dystrophic resident nuclei. When transplanted into NSG-mdx-Δ51mice carrying a mutation of exon 51, genetically corrected human myogenic cells produce dystrophin at much higher level than WT cells, well in the therapeutic range, and lead to force recovery even with an engraftment of only 3–5%. This level of dystrophin production is an important step towards clinical efficacy for cell therapy.
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Dates et versions

hal-04603972 , version 1 (10-06-2024)

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Francesco Galli, Laricia Bragg, Maira Rossi, Daisy Proietti, Laura Perani, et al.. Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy. EMBO Molecular Medicine, 2024, 16 (4), pp.927 - 944. ⟨10.1038/s44321-024-00031-3⟩. ⟨hal-04603972⟩
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