Cited by 501CRISPR and Genetic EngineeringRNA Interference and Gene DeliveryRNA regulation and disease

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Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing

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Yin, Hao, Song, Chun-Qing, Suresh, Sneha, Wu, Qiongqiong, Walsh, Stephen, Rhym, Luke Hyunsik, Mintzer, Esther, Bolukbasi, Mehmet Fatih, Zhu, Lihua Julie, Kauffman, Kevin, Mou, Haiwei, Oberholzer, Alicia, Ding, Junmei, Kwan, Suet-Yan, Bogorad, Roman L, Zatsepin, Timofei, Koteliansky, Victor, Wolfe, Scot A, Xue, Wen, Langer, Robert, Anderson, Daniel G·2017·Nature Biotechnology

DOI 10.1038/nbt.4005PMC PMC5901668

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Abstract

Efficient genome editing with Cas9-sgRNA in vivo has required the use of viral delivery systems, which have limitations for clinical applications. Translational efforts to develop other RNA therapeutics have shown that judicious chemical modification of RNAs can improve therapeutic efficacy by reducing susceptibility to nuclease degradation. Guided by the structure of the Cas9-sgRNA complex, we identify regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and we develop an optimal set of chemical modifications for in vivo applications. Using lipid nanoparticle formulations of these enhanced sgRNAs (e-sgRNA) and mRNA encoding Cas9, we show that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver. Serum Pcsk9 is reduced to undetectable levels, and cholesterol levels are significantly lowered about 35% to 40% in animals. This strategy may enable non-viral, Cas9-based genome editing in the liver in clinical settings.

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Authors: Yin, H., Song, C.-Q., Suresh, S., Wu, Q., Walsh, S., Rhym, L. H., Mintzer, E., Bolukbasi, M. F., Zhu, L. J., Kauffman, K., Mou, H., Oberholzer, A., Ding, J., Kwan, S.-Y., Bogorad, R. L., Zatsepin, T., Koteliansky, V., Wolfe, S. A., Xue, W., Langer, R., & Anderson, D. G.
Affiliations: Koch Institute for Integrative Cancer Research At MIT (US)
University of Massachusetts Chan Medical School (US)
Skolkovo Institute of Science and Technology (RU)
Harvard–MIT Division of Health Sciences and Technology (US)
Corresponding author: Anderson, Daniel G
ORCID: Yin, Hao
Song, Chun-Qing
Suresh, Sneha
Walsh, Stephen
Rhym, Luke Hyunsik
Mintzer, Esther
Bolukbasi, Mehmet Fatih
Zhu, Lihua Julie
Kauffman, Kevin
Mou, Haiwei
Bogorad, Roman L
Zatsepin, Timofei
Wolfe, Scot A
Xue, Wen
Anderson, Daniel G
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2017-11-13
Volume: 35
Issue: 12
Pages: 1179-1187
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt.4005
PMC: PMC5901668
OpenAlex: W2770127492
Cited by: 499
References: 48
Citations by year: 2026: 39 · 2025: 31 · 2024: 53 · 2023: 63 · 2022: 75 · 2021: 64 · 2020: 52 · 2019: 51 · 2018: 71
FWCI: 19.43
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders: Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
Skolkovo Institute of Science and Technology
National Institutes of Health
National Heart, Lung, and Blood Institute (P01HL131471, DP2HL137167)
National Cancer Institute (U54CA151884, R00CA169512, P30CA014051)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords: Cas9, in vivo gene editing, non-viral delivery, lipid nanoparticle delivery, PCSK9, cholesterol lowering, RNA therapeutics, nuclease resistance
MeSH terms: Proprotein Convertase 9, Gene Editing, RNA, Guide, CRISPR-Cas Systems, Animals, Liver, Nucleic Acid Conformation, Gene Transfer Techniques, Mice, Nanoparticles, CRISPR-Cas Systems

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Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing

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