MIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

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

Author(s)
Yin, Hao; Song, Chun-Qing; Suresh, Sneha; Wu, Qiongqiong; Walsh, Stephen C; Rhym, Luke Hyunsik; Mintzer, Esther; Bolukbasi, Mehmet Fatih; Zhu, Lihua Julie; Kauffman, Kevin John; Mou, Haiwei; Oberholzer, Alicia; Ding, Junmei; Kwan, Suet-Yan; Bogorad, Roman; Zatsepin, Timofei; Koteliansky, Victor; Wolfe, Scot A; Xue, Wen; Langer, Robert; Langer, Robert S; Anderson, Daniel Griffith; ... Show more Show less
Thumbnail
DownloadAccepted version (1.599Mb)
Terms of use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Metadata
Show full item record
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.
Date issued
2017-11
URI
https://hdl.handle.net/1721.1/121981
Department
Massachusetts Institute of Technology. Department of Chemical Engineering; Harvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Institute for Medical Engineering & Science; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Citation
Yin, Hao et al. "Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing." Nature Biotechnology 35, 12 (November 2017): 1179-1187 © 2017 Nature Publishing Group
Version: Author's final manuscript
ISSN
1087-0156
1546-1696

Collections
  • MIT Open Access Articles

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries
PrivacyPermissionsAccessibilityContact us
MIT
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.