Journal
SCIENCE
Volume 358, Issue 6366, Pages 1019-1027Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaq0180
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Funding
- National Institute of General Medical Sciences [T32GM007753]
- Paul and Daisy Soros Fellowship
- NIH F30 National Research Service Award [1F30-CA210382]
- NIH [1R01-HG009761, 1R01-MH110049, 1DP1-HL141201]
- Howard Hughes Medical Institute
- New York Stem Cell Foundation
- Simons Foundation
- Paul G. Allen Family Foundation
- Vallee Foundation
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Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI CRISPR-Cas systems contain the programmable single-effector RNA-guided ribonuclease Cas13. We profiled type VI systems in order to engineer a Cas13 ortholog capable of robust knockdown and demonstrated RNA editing by using catalytically inactive Cas13 (dCas13) to direct adenosine-to-inosine deaminase activity by ADAR2 (adenosine deaminase acting on RNA type 2) to transcripts in mammalian cells. This system, referred to as RNA Editing for Programmable A to I Replacement (REPAIR), which has no strict sequence constraints, can be used to edit full-length transcripts containing pathogenic mutations. We further engineered this system to create a high-specificity variant and minimized the system to facilitate viral delivery. REPAIR presents a promising RNA-editing platform with broad applicability for research, therapeutics, and biotechnology.
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