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| Item Type: | Article |
|---|---|
| Title: | Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy |
| Creators: |
Escobar, H.  ORCID: https://orcid.org/0000-0002-8128-7845, Di Francescantonio, S. ORCID: https://orcid.org/0000-0002-4815-491X, Smirnova, J., Graf, R. ORCID: https://orcid.org/0000-0002-5400-9938, Müthel, S. ORCID: https://orcid.org/0000-0002-3525-8859, Marg, A. ORCID: https://orcid.org/0000-0003-3673-4244, Zhogov, A., Krishna, S. ORCID: https://orcid.org/0009-0008-8974-0721, Metzler, E. ORCID: https://orcid.org/0000-0003-1735-6364, Petkova, M., Daumke, O. ORCID: https://orcid.org/0000-0002-6190-1414, Kühn, R. ORCID: https://orcid.org/0000-0003-1694-9803 and Spuler, S. ORCID: https://orcid.org/0000-0002-0155-1117
|
| Abstract: | Dystrophy-associated fer-1-like protein (dysferlin) conducts plasma membrane repair. Mutations in the DYSF gene cause a panoply of genetic muscular dystrophies. We targeted a frequent loss-of-function, DYSF exon 44, founder frameshift mutation with mRNA-mediated delivery of SpCas9 in combination with a mutation-specific sgRNA to primary muscle stem cells from two homozygous patients. We observed a consistent >60% exon 44 re-framing, rescuing a full-length and functional dysferlin protein. A new mouse model harboring a humanized Dysf exon 44 with the founder mutation, hEx44mut, recapitulates the patients’ phenotype and an identical re-framing outcome in primary muscle stem cells. Finally, gene-edited murine primary muscle stem-cells are able to regenerate muscle and rescue dysferlin when transplanted back into hEx44mut hosts. These findings are the first to show that a CRISPR-mediated therapy can ameliorate dysferlin deficiency. We suggest that gene-edited primary muscle stem cells could exhibit utility, not only in treating dysferlin deficiency syndromes, but also perhaps other forms of muscular dystrophy. |
| Keywords: | Animal Disease Models, CRISPR-Cas Systems, Dysferlin, Exons, Frameshift Mutation, Gene Editing, Genetic Therapy, Limb-Girdle Muscular Dystrophies, Membrane Proteins, Muscular Dystrophies, Skeletal Muscle, Stem Cells, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 16 |
| Number: | 1 |
| Page Range: | 120 |
| Date: | 2 January 2025 |
| Official Publication: | https://doi.org/10.1038/s41467-024-55086-0 |
| PubMed: | View item in PubMed |
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