RNA-guided cell targeting with CRISPR/RfxCas13d collateral activity in human cells
Open accessAbstract
While single-cell sequencing has allowed rapid identification of novel cell types or states and associated RNA markers, functional studies remain challenging due to the lack of tools that are able to target specific cells based on these markers. Here we show that targeting a single marker RNA with CRISPR/RfxCas13d led to collateral transcriptome destruction in human cells, which can be harnessed to inhibit cell proliferation or to suppress cell state transition.
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Significant unintended editing has been reported for CasRx, hampering its clinical progress.
“however, significant unintended editing has been reported hampering its clinical progress (8, 9)”
From Characterization of RNA editing and gene therapy with a compact CRISPR-Cas13 in the retina (2024) · cites this paper as [9]
The Results report substantial unintended, transcriptome-wide RNA degradation by RfxCas13d in human cells and call for caution in its use for targeted RNA knockdown. They describe collateral RNA degradation rather than unintended editing, and do not establish that it has hampered clinical progress; the paper instead discusses potential therapeutic development. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRNA editing with CRISPR-Cas13 has emerged as a powerful tool for transient control of gene expression, although recurrent reports of collateral activity are a hurdle for clinical translation.
“RNA editing with CRISPR-Cas13 has emerged as a powerful tool for transient control of gene expression, although recurrent reports of collateral activity are a hurdle for clinical translation.”
From Characterization of RNA editing and gene therapy with a compact CRISPR-Cas13 in the retina (2024) · cites this paper as [9]
The Results report collateral RNA degradation by RfxCas13d in human cells and call for caution in using it for targeted RNA knockdown, supporting the concern about collateral activity. They do not establish the claim that RNA editing provides transient control of gene expression or explicitly assess clinical translation. The paper also describes earlier eukaryotic studies as finding no collateral activity and later reports as conflicting. (LLM, conf=0.86)
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Cites
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · see citing works
Programmable RNA targeting with the single-protein CRISPR effector Cas7-11
Özcan, A., Krajeski, R., Ioannidi, E., Lee, B., Gardner, A., Makarova, K. S., Koonin, E. V., Abudayyeh, O. O., & Gootenberg, J. S. (2021) · Nature · doi:10.1038/s41586-021-03886-5 · Cited by 263 · see citing works
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Research works printed but not linked: 1
- Ai, Y., Liang, D. & Wilusz, J. E. CRISPR/Cas13 effectors have differing extents of off- target effects that limit their utility in eukaryotic cells. bioRxiv, 2021.2011.2004.467323, (2021).
Cited by
Sorted by citations
High-fidelity Cas13 variants for targeted RNA degradation with minimal collateral effects
Tong, H., Huang, J., Xiao, Q., He, B., Dong, X., Liu, Y., Yang, X., Han, D., Wang, Z., Wang, X., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01419-7 · Cited by 230 · see citing works
Efficient combinatorial targeting of RNA transcripts in single cells with Cas13 RNA Perturb-seq
Wessels, H.-H., Méndez-Mancilla, A., Hao, Y., Papalexi, E., Mauck, W. M., Lu, L., Morris, J. A., Mimitou, E. P., Smibert, P., Sanjana, N. E., et al. (2023) · Nature Methods · doi:10.1038/s41592-022-01705-x · Cited by 79 · see citing works
Deep learning and CRISPR-Cas13d ortholog discovery for optimized RNA targeting
Wei, J., Lotfy, P., Faizi, K., Baungaard, S., Gibson, E., Wang, E., Slabodkin, H., Kinnaman, E., Chandrasekaran, S., Kitano, H., et al. (2021) · doi:10.1101/2021.09.14.460134 · Cited by 67 · see citing works
Characterization of RNA editing and gene therapy with a compact CRISPR-Cas13 in the retina
Kumar, S., Hsiao, Y.-W., Wong, V. H. Y., Aubin, D., Wang, J.-H., Lisowski, L., Rakoczy, E. P., Li, F., Alarcon-Martinez, L., Gonzalez-Cordero, A., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2408345121 · Cited by 19 · see citing works
Optimization of specific RNA knockdown in mammalian cells with CRISPR-Cas13
Burris, B. J. D., Molina Vargas, A. M., Park, B. J., & O'Connell, M. R. (2022) · Methods · doi:10.1016/j.ymeth.2022.08.007 · Cited by 13 · see citing works
- Authors
- Shi, P., Murphy, M. R., Aparicio, A. O., Kesner, J. S., Fang, Z., Chen, Z., Trehan, A., & Wu, X.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Shi, Peiguo
- Wu, Xuebing
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2021-11-30
- OpenAlex
- W3217154297
- Cited by
- 21
- References
- 2
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- American Heart Association (P30CA013696)
- Pershing Square Sohn Cancer Research Alliance
- National Institutes of Health (1s10od020056-01, Support Grant P30CA013696)
- NIH Office of the Director (S10OD020056, S10RR027050)
- National Cancer Institute (P30CA013696)
- National Institute of General Medical Sciences (DP2GM140977)
- National Center for Research Resources (S10RR027050)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- CRISPR-Cas13d, cell proliferation inhibition, cell state transitions
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