A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD
Abstract An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55548-5 |
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| author | Tristan X. McCallister Colin K. W. Lim Mayuri Singh Sijia Zhang Najah S. Ahsan William M. Terpstra Alisha Y. Xiong M. Alejandra Zeballos C Jackson E. Powell Jenny Drnevich Yifei Kang Thomas Gaj |
| author_facet | Tristan X. McCallister Colin K. W. Lim Mayuri Singh Sijia Zhang Najah S. Ahsan William M. Terpstra Alisha Y. Xiong M. Alejandra Zeballos C Jackson E. Powell Jenny Drnevich Yifei Kang Thomas Gaj |
| author_sort | Tristan X. McCallister |
| collection | DOAJ |
| description | Abstract An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD. |
| format | Article |
| id | doaj-art-6e7f8a5eb0cd45f7bafc7b6ce19566bd |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6e7f8a5eb0cd45f7bafc7b6ce19566bd2025-01-12T12:30:20ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55548-5A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTDTristan X. McCallister0Colin K. W. Lim1Mayuri Singh2Sijia Zhang3Najah S. Ahsan4William M. Terpstra5Alisha Y. Xiong6M. Alejandra Zeballos C7Jackson E. Powell8Jenny Drnevich9Yifei Kang10Thomas Gaj11Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignHigh-Performance Biological Computing, Roy J. Carver Biotechnology Center, University of Illinois Urbana-ChampaignHigh-Performance Biological Computing, Roy J. Carver Biotechnology Center, University of Illinois Urbana-ChampaignDepartment of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-ChampaignAbstract An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.https://doi.org/10.1038/s41467-024-55548-5 |
| spellingShingle | Tristan X. McCallister Colin K. W. Lim Mayuri Singh Sijia Zhang Najah S. Ahsan William M. Terpstra Alisha Y. Xiong M. Alejandra Zeballos C Jackson E. Powell Jenny Drnevich Yifei Kang Thomas Gaj A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD Nature Communications |
| title | A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD |
| title_full | A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD |
| title_fullStr | A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD |
| title_full_unstemmed | A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD |
| title_short | A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD |
| title_sort | high fidelity crispr cas13 system improves abnormalities associated with c9orf72 linked als ftd |
| url | https://doi.org/10.1038/s41467-024-55548-5 |
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