Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
EMBO molecular medicine - 16(2024), 4 vom: 24. Apr., Seite 927-944 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Galli, Francesco [VerfasserIn] |
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| Links: |
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| Themen: |
Cell Therapy |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s44321-024-00031-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369284216 |
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| 245 | 1 | 0 | |a Cell-mediated exon skipping normalizes dystrophin expression and muscle function in a new mouse model of Duchenne Muscular Dystrophy |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Exon Skipping | |
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| 650 | 4 | |a Regenerative Medicine | |
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| 700 | 1 | |a Bragg, Laricia |e verfasserin |4 aut | |
| 700 | 1 | |a Rossi, Maira |e verfasserin |4 aut | |
| 700 | 1 | |a Proietti, Daisy |e verfasserin |4 aut | |
| 700 | 1 | |a Perani, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Bagicaluppi, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Tonlorenzi, Rossana |e verfasserin |4 aut | |
| 700 | 1 | |a Sibanda, Tendai |e verfasserin |4 aut | |
| 700 | 1 | |a Caffarini, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Talapatra, Avraneel |e verfasserin |4 aut | |
| 700 | 1 | |a Santoleri, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Meregalli, Mirella |e verfasserin |4 aut | |
| 700 | 1 | |a Bano-Otalora, Beatriz |e verfasserin |4 aut | |
| 700 | 1 | |a Bigot, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Bozzoni, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Bonini, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Mouly, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Torrente, Yvan |e verfasserin |4 aut | |
| 700 | 1 | |a Cossu, Giulio |e verfasserin |4 aut | |
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