{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:34:02Z","timestamp":1790278442252,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T00:00:00Z","timestamp":1723766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Wave Life Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>AIMers are short, chemically modified oligonucleotides that induce A-to-I RNA editing through interaction with endogenous adenosine deaminases acting on RNA (ADAR) enzymes. Here, we describe the development of new AIMer designs with base, sugar and backbone modifications that improve RNA editing efficiency over our previous design. AIMers incorporating a novel pattern of backbone and 2\u2032 sugar modifications support enhanced editing efficiency across multiple sequences. Further efficiency gains were achieved through incorporation of an N-3-uridine (N3U), in place of cytidine (C), in the \u2018orphan base\u2019 position opposite the edit site. Molecular modeling suggests that N3U might enhance ADAR catalytic activity by stabilizing the AIMer-ADAR interaction and potentially reducing the energy required to flip the target base into the active site. Supporting this hypothesis, AIMers containing N3U consistently enhanced RNA editing over those containing C across multiple target sequences and multiple nearest neighbor sequence combinations. AIMers combining N3U and the novel pattern of 2\u2032 sugar chemistry and backbone modifications improved RNA editing both in vitro and in vivo. We provide detailed N3U synthesis methods and, for the first time, explore the impact of N3U and its analogs on ADAR-mediated RNA editing efficiency and targetable sequence space.<\/jats:p>","DOI":"10.1093\/nar\/gkae681","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T10:07:39Z","timestamp":1723802859000},"page":"10068-10084","source":"Crossref","is-referenced-by-count":20,"title":["Rational design of base, sugar\u00a0and backbone modifications improves ADAR-mediated RNA editing"],"prefix":"10.1093","volume":"52","author":[{"given":"Genliang","family":"Lu","sequence":"first","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikdu","family":"Shivalila","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Monian","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yu","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Harding","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stearne","family":"Briem","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Byrne","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyse","family":"Faraone","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Friend","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Huth","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Kawamoto","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayakanthan","family":"Kumarasamy","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Lamattina","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Longo","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McGlynn","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Molski","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianli","family":"Pan","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Pu","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Purcell-Estabrook","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Rossi","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephany","family":"Standley","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Thomas","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Walen","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailin","family":"Yang","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pachamuthu","family":"Kandasamy","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4690-7543","authenticated-orcid":false,"given":"Chandra","family":"Vargeese","sequence":"additional","affiliation":[{"name":"Wave Life Sciences , Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"2024092307452652800_B1","doi-asserted-by":"crossref","first-page":"1092913","DOI":"10.3389\/fnmol.2023.1092913","article-title":"Programmable RNA editing with endogenous ADAR enzymes - a feasible option for the treatment of inherited retinal disease?","volume":"16","author":"Bellingrath","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"2024092307452652800_B2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13059-019-1725-0","article-title":"Collateral damage: benchmarking off-target effects in genome editing","volume":"20","author":"Carroll","year":"2019","journal-title":"Genome Biol."},{"key":"2024092307452652800_B3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/bs.enz.2017.03.006","article-title":"Adenosine deaminases that act on RNA (ADARs)","volume":"41","author":"Wang","year":"2017","journal-title":"Enzymes"},{"key":"2024092307452652800_B4","doi-asserted-by":"crossref","first-page":"6865","DOI":"10.1021\/jacs.0c13319","article-title":"Rational design of RNA editing guide strands: cytidine analogs at the orphan position","volume":"143","author":"Doherty","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"2024092307452652800_B5","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1038\/s41467-018-04580-3","article-title":"In vivo base editing of post-mitotic sensory cells","volume":"9","author":"Yeh","year":"2018","journal-title":"Nat. Commun."},{"key":"2024092307452652800_B6","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1038\/s41587-023-01927-0","article-title":"Precision RNA base editing with engineered and endogenous effectors","volume":"41","author":"Pfeiffer","year":"2023","journal-title":"Nat. Biotechnol."},{"key":"2024092307452652800_B7","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/ncomms1324","article-title":"Predicting sites of ADAR editing in double-stranded RNA","volume":"2","author":"Eggington","year":"2011","journal-title":"Nat. Commun."},{"key":"2024092307452652800_B8","doi-asserted-by":"crossref","first-page":"E3295","DOI":"10.1073\/pnas.1212548109","article-title":"Mechanistic insights into editing-site specificity of ADARs","volume":"109","author":"Kuttan","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2024092307452652800_B9","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/nsmb.3203","article-title":"Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity","volume":"23","author":"Matthews","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2024092307452652800_B10","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/s41587-022-01225-1","article-title":"Endogenous ADAR-mediated RNA editing in non-human primates using stereopure chemically modified oligonucleotides","volume":"40","author":"Monian","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"2024092307452652800_B11","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2024092307452652800_B12","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1021\/jo00935a012","article-title":"Rearrangement of anhydropyrimidine nucleosides in liquid hydrogen fluoride. Mechanism, scope, and synthetic studies","volume":"39","author":"Polazzi","year":"1974","journal-title":"J. Org. Chem."},{"key":"2024092307452652800_B13","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1016\/S0040-4020(01)93406-4","article-title":"Synthesis of 1-(2\u2032-O-methyl-\u03b2-d-ribofuranosyl)-uracil (2\u2032-O-methyluridine) and 3-(2\u2032-O-methyl-\u03b2-d-ribofuranosyl)uracil","volume":"29","author":"Haines","year":"1973","journal-title":"Tetrahedron"},{"key":"2024092307452652800_B14","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.1093\/nar\/gkac037","article-title":"Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS","volume":"50","author":"Kandasamy","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2024092307452652800_B15","doi-asserted-by":"crossref","first-page":"5443","DOI":"10.1093\/nar\/gkac018","article-title":"Control of backbone chemistry and chirality boost oligonucleotide splice switching activity","volume":"50","author":"Kandasamy","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2024092307452652800_B16","doi-asserted-by":"crossref","first-page":"4126","DOI":"10.1093\/nar\/gkad268","article-title":"Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference","volume":"51","author":"Liu","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"2024092307452652800_B17","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nbt.3948","article-title":"Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides","volume":"35","author":"Iwamoto","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"2024092307452652800_B18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/crispr.2018.0014","article-title":"EditR: a method to quantify base editing from sanger sequencing","volume":"1","author":"Kluesner","year":"2018","journal-title":"CRISPR J."},{"key":"2024092307452652800_B19","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/dvdy.24183","article-title":"Poly peak parser: method and software for identification of unknown indels using sanger sequencing of polymerase chain reaction products","volume":"243","author":"Hill","year":"2014","journal-title":"Dev. Dyn."},{"key":"2024092307452652800_B20","volume-title":"R Foundation for Statistical Computing","author":"Team","year":"2022"},{"key":"2024092307452652800_B21","first-page":"319","author":"Berthold","year":"2008"},{"key":"2024092307452652800_B22","volume-title":"An R Companion to Applied Regression","author":"Fox","year":"2019","edition":"3rd edn"},{"key":"2024092307452652800_B23","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/bimj.200810425","article-title":"Simultaneous inference in general parametric models","volume":"50","author":"Hothorn","year":"2008","journal-title":"Biom. J."},{"key":"2024092307452652800_B24","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cell.2012.05.017","article-title":"The structure of human argonaute-2 in complex with miR-20a","volume":"150","author":"Elkayam","year":"2012","journal-title":"Cell"},{"key":"2024092307452652800_B25","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1126\/science.1221551","article-title":"The crystal structure of human Argonaute2","volume":"336","author":"Schirle","year":"2012","journal-title":"Science"},{"key":"2024092307452652800_B26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v095.i01","article-title":"Various versatile variances: an object-oriented implementation of clustered covariances in R","volume":"95","author":"Zeileis","year":"2020","journal-title":"J. Stat. Softw."},{"key":"2024092307452652800_B27","doi-asserted-by":"crossref","first-page":"e0146021","DOI":"10.1371\/journal.pone.0146021","article-title":"Dose-response analysis using R","volume":"10","author":"Ritz","year":"2015","journal-title":"PLoS One"},{"key":"2024092307452652800_B28","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1146\/annurev.genet.34.1.499","article-title":"Functions and mechanisms of RNA editing","volume":"34","author":"Gott","year":"2000","journal-title":"Annu. Rev. Genet."},{"key":"2024092307452652800_B29","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.1038\/s41467-020-18862-2","article-title":"High-throughput mutagenesis reveals unique structural features of human ADAR1","volume":"11","author":"Park","year":"2020","journal-title":"Nat. Commun."},{"key":"2024092307452652800_B30","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1021\/acschembio.5b00711","article-title":"A phenotypic screen for functional mutants of Human adenosine deaminase acting on RNA 1","volume":"10","author":"Wang","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"2024092307452652800_B31","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1038\/s41467-022-28841-4","article-title":"Landscape of adenosine-to-inosine RNA recoding across human tissues","volume":"13","author":"Gabay","year":"2022","journal-title":"Nat. Commun."},{"key":"2024092307452652800_B32","doi-asserted-by":"crossref","first-page":"12875","DOI":"10.1021\/bi001383g","article-title":"Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities","volume":"39","author":"Lehmann","year":"2000","journal-title":"Biochemistry"},{"key":"2024092307452652800_B33","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1021\/jm00059a007","article-title":"Uniformly modified 2\u2032-deoxy-2\u2032-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets","volume":"36","author":"Kawasaki","year":"1993","journal-title":"J. Med. Chem."},{"key":"2024092307452652800_B34","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/S0140-6736(16)31009-1","article-title":"Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials","volume":"388","author":"Viney","year":"2016","journal-title":"Lancet"},{"key":"2024092307452652800_B35","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1056\/NEJMra1910234","article-title":"Alpha(1)-antitrypsin deficiency","volume":"382","author":"Strnad","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"2024092307452652800_B36","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1093\/nar\/gkac897","article-title":"ADAR activation by inducing a syn conformation at guanosine adjacent to an editing site","volume":"50","author":"Doherty","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/advance-article-pdf\/doi\/10.1093\/nar\/gkae681\/59209687\/gkae681.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/advance-article-pdf\/doi\/10.1093\/nar\/gkae681\/59209687\/gkae681.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T07:46:03Z","timestamp":1727077563000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/52\/17\/10068\/7734167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,16]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,8,16]]},"published-print":{"date-parts":[[2024,9,23]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkae681","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,9,23]]},"published":{"date-parts":[[2024,8,16]]}}}