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dc.contributor.authorBamidele, Nathan
dc.contributor.authorZhang, Han
dc.contributor.authorDong, Xiaolong
dc.contributor.authorCheng, Haoyang
dc.contributor.authorGaston, Nicholas
dc.contributor.authorFeinzig, Hailey
dc.contributor.authorCao, Hanbing
dc.contributor.authorKelly, Karen
dc.contributor.authorWatts, Jonathan K
dc.contributor.authorXie, Jun
dc.contributor.authorGao, Guangping
dc.contributor.authorSontheimer, Erik J
dc.date.accessioned2024-04-02T15:58:25Z
dc.date.available2024-04-02T15:58:25Z
dc.date.issued2024-02-17
dc.identifier.citationBamidele N, Zhang H, Dong X, Cheng H, Gaston N, Feinzig H, Cao H, Kelly K, Watts JK, Xie J, Gao G, Sontheimer EJ. Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope. Nat Commun. 2024 Feb 17;15(1):1458. doi: 10.1038/s41467-024-45763-5. PMID: 38368418; PMCID: PMC10874451.en_US
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-024-45763-5en_US
dc.identifier.pmid38368418
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53258
dc.description.abstractNme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we engineer Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first use domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex. These domain-inlaid Nme2Cas9 variants exhibit shifted editing windows and increased activity in comparison to the N-terminally fused Nme2-ABE. We next expand the editing scope by swapping the Nme2Cas9 PAM-interacting domain with that of SmuCas9, which we had previously defined as recognizing a single-cytidine PAM. We then use these enhancements to introduce therapeutically relevant edits in a variety of cell types. Finally, we validate domain-inlaid Nme2-ABEs for single-AAV delivery in vivo.en_US
dc.language.isoenen_US
dc.relation.ispartofNature Communicationsen_US
dc.relation.urlhttps://doi.org/10.1038/s41467-024-45763-5en_US
dc.rightsOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCRISPR-Cas9 genome editingen_US
dc.subjectMolecular medicineen_US
dc.subjectTargeted gene repairen_US
dc.titleDomain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scopeen_US
dc.typeJournal Articleen_US
dc.source.journaltitleNature communications
dc.source.volume15
dc.source.issue1
dc.source.beginpage1458
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journalNature communications
refterms.dateFOA2024-04-02T15:58:27Z
dc.contributor.departmentBiochemistry and Molecular Biotechnologyen_US
dc.contributor.departmentHorae Gene Therapy Centeren_US
dc.contributor.departmentLi Weibo Institute for Rare Diseases Researchen_US
dc.contributor.departmentMicrobiology and Physiological Systemsen_US
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentNeuroNexus Instituteen_US
dc.contributor.departmentProgram in Molecular Medicineen_US
dc.contributor.departmentRNA Therapeutics Instituteen_US
dc.contributor.studentNathan Bamidele
dc.contributor.studentHan Zhang
dc.contributor.studentHaoyang Cheng
dc.contributor.studentNicholas Gaston
dc.contributor.studentHanbing Cao
dc.description.thesisprogramInterdisciplinary


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Open Access: This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless
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included in the article’s Creative Commons licence and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2024
Except where otherwise noted, this item's license is described as Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2024