Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy.
Cell Therapy
Duchenne Muscular Dystrophy
Exon Skipping
Mesoangioblast
Regenerative Medicine
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
04 Mar 2024
04 Mar 2024
Historique:
received:
27
02
2023
accepted:
22
01
2024
revised:
12
01
2024
medline:
5
3
2024
pubmed:
5
3
2024
entrez:
4
3
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38438561
doi: 10.1038/s44321-024-00031-3
pii: 10.1038/s44321-024-00031-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : UKRI | Medical Research Council (MRC)
ID : MR/P016006/1
Organisme : UKRI | Medical Research Council (MRC)
ID : MR/S015116/1
Organisme : Wellcome Trust (WT)
ID : HICF 107572
Organisme : Duchenne Parent Project
ID : ERC-2019-ADG 884952
Informations de copyright
© 2024. The Author(s).
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