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Myospreader improves gene editing in skeletal muscle by myonuclear propagation.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 5/7/2024, Vol. 121 Issue 19, p1-9, 21p
- Publication Year :
- 2024
-
Abstract
- Successful CRISPR/Cas9-based gene editing in skeletal muscle is dependent on efficient propagation of Cas9 to all myonuclei in the myofiber. However, nuclear-targeted gene therapy cargos are strongly restricted to their myonuclear domain of origin. By screening nuclear localization signals and nuclear export signals, we identify "Myospreader," a combination of short peptide sequences that promotes myonuclear propagation. Appending Myospreader to Cas9 enhances protein stability and myonuclear propagation in myoblasts and myofibers. AAV-delivered Myospreader dCas9 better inhibits transcription of toxic RNA in a myotonic dystrophy mouse model. Furthermore, Myospreader Cas9 achieves higher rates of gene editing in CRISPR reporter and Duchenne muscular dystrophy mouse models. Myospreader reveals design principles relevant to all nuclear-targeted gene therapies and highlights the importance of the spatial dimension in therapeutic development. [ABSTRACT FROM AUTHOR]
- Subjects :
- GENOME editing
SKELETAL muscle
GENE therapy
DUCHENNE muscular dystrophy
CRISPRS
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 121
- Issue :
- 19
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 178011316
- Full Text :
- https://doi.org/10.1073/pnas.2321438121