期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-018-04048-4
关键词
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资金
- Paul G. Allen Frontiers Group
- Thorek Memorial Foundation
- US National Institutes of Health (NIH) [R01DA036865, R21DA041878, UG3TR002142, UH3TR000505, P30AR066527, R41GM119914]
- NIH Director's New Innovator Award [DP2OD008586]
- US National Science Foundation (NSF) Faculty Early Career Development (CAREER) Award [CBET-1151035]
- American Heart Association Scientist Development Grant [10SDG3060033]
- National Science Foundation Graduate Research Fellowship
- American Heart Association Mid-Atlantic Affiliate Predoctoral Fellowship
- Hartwell Foundation Postdoctoral Fellowship
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UG3TR002142, UH2TR000505] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA036865] Funding Source: NIH RePORTER
CRISPR-Cas9 transcriptional repressors have emerged as robust tools for disrupting gene regulation in vitro but have not yet been adapted for systemic delivery in adult animal models. Here we describe a Staphylococcus aureus Cas9-based repressor (dSaCas9(KRAB)) compatible with adeno-associated viral (AAV) delivery. To evaluate dSaCas9(KRAB) efficacy for gene silencing in vivo, we silenced transcription of Pcsk9, a regulator of cholesterol levels, in the liver of adult mice. Systemic administration of a dual-vector AAV8 system expressing dSaCas9(KRAB) and a Pcsk9-targeting guide RNA (gRNA) results in significant reductions of serum Pcsk9 and cholesterol levels. Despite a moderate host response to dSaCas9(KRAB) expression, Pcsk9 repression is maintained for 24 weeks after a single treatment, demonstrating the potential for long-term gene silencing in post-mitotic tissues with dSaCas9(KRAB). In vivo programmable gene silencing enables studies that link gene regulation to complex phenotypes and expands the CRISPR-Cas9 perturbation toolbox for basic research and gene therapy applications.
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