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dc.contributor.authorYin, Hao
dc.contributor.authorSong, Chun-Qing
dc.contributor.authorMintzer, Esther
dc.contributor.authorBolukbasi, Mehmet F.
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorMou, Haiwei
dc.contributor.authorKwan, Suet-Yan
dc.contributor.authorWolfe, Scot A.
dc.contributor.authorXue, Wen
dc.contributor.authorAnderson, Daniel G.
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:22:56Z
dc.date.available2022-08-23T17:22:56Z
dc.date.issued2017-12-01
dc.date.submitted2018-04-26
dc.identifier.citation<p>Nat Biotechnol. 2017 Dec;35(12):1179-1187. doi: 10.1038/nbt.4005. Epub 2017 Nov 13. <a href="https://doi.org/10.1038/nbt.4005">Link to article on publisher's site</a></p>
dc.identifier.issn1087-0156 (Linking)
dc.identifier.doi10.1038/nbt.4005
dc.identifier.pmid29131148
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48851
dc.description<p>Full list of authors omitted for brevity. For full list see article.</p>
dc.description.abstractEfficient 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=29131148&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901668/
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCell and Developmental Biology
dc.subjectGenetics and Genomics
dc.subjectTherapeutics
dc.titleStructure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing
dc.typeJournal Article
dc.source.journaltitleNature biotechnology
dc.source.volume35
dc.source.issue12
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/rti_pubs/6
dc.identifier.contextkey12026041
html.description.abstract<p>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.</p>
dc.identifier.submissionpathrti_pubs/6
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.contributor.departmentRNA Therapeutics Institute
dc.source.pages1179-1187


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