{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:07:11Z","timestamp":1784189231306,"version":"3.55.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Simons Foundation Autism Research Initiative-Pilot Award","award":["646844"],"award-info":[{"award-number":["646844"]}]},{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"publisher","award":["AR220030"],"award-info":[{"award-number":["AR220030"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Developmental Disabilities Research Center","award":["P50HD103556"],"award-info":[{"award-number":["P50HD103556"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein-truncating variants caused by stop codons are the most prevalent class of rare variant mutations in neurodevelopmental diseases, with UGA codons being most common. Suppressor transfer RNA (sup-tRNA) has therapeutic potential for premature termination codon (PTC) rescue but has thus far underperformed by traditional AAV delivery platforms, and progress has been hampered by the lack of methods to non-invasively assess in vivo activity in mammalian brain. To fill this material gap, we utilize transcranial in vivo bioluminescence imaging data from a luciferase-UGA mouse model to optimize viral payloads with sup-tRNA genes. These data demonstrate that U6 promoter-driven and single-stranded AAV2\/9 constructs show variable and dose-dependent activity, whereas self-complementary AAV2\/9 with the tRNA in a minimal 100-bp genomic context provides broad and efficacious PTC rescue. Further, payload tRNA multiplexing and use of tRNA introns enable efficacy of low viral titers and sustained rescue. tRNA sequencing of scAAV-delivered ArgUCA sup-tRNA in brain demonstrates no effects on endogenous tRNA levels, their acylation, or processing, and these features are also maintained in the delivered ArgUCA sup-tRNA. Collectively, this work defines a scalable strategy for precision UGA PTC stop codon suppression, supporting development of durable genetic rescue therapies for neurodevelopmental disorders in the mammalian brain.<\/jats:p>","DOI":"10.1093\/nar\/gkag695","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T07:35:32Z","timestamp":1784187332000},"source":"Crossref","is-referenced-by-count":0,"title":["Programmed repair of disease-causing UGA premature termination codons in mammalian brain"],"prefix":"10.1093","volume":"54","author":[{"given":"Ahmad","family":"Al\u00a0Saneh","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa , Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel","family":"Gissot","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa , Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-2744","authenticated-orcid":false,"given":"Christopher A","family":"Ahern","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa , Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2026071603352545500_B1","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/ng.3789","article-title":"Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples","volume":"49","author":"Kosmicki","year":"2017","journal-title":"Nat Genet"},{"key":"2026071603352545500_B2","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1111\/cge.13243","article-title":"Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features","volume":"93","author":"Moutton","year":"2018","journal-title":"Clin Genet"},{"key":"2026071603352545500_B3","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1136\/jmedgenet-2015-103069","article-title":"WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome","volume":"52","author":"DeSanto","year":"2015","journal-title":"J Med Genet"},{"key":"2026071603352545500_B4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13229-020-00330-9","article-title":"SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells?","volume":"11","author":"Kruth","year":"2020","journal-title":"Molecular Autism"},{"key":"2026071603352545500_B5","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/ng.3303","article-title":"Excess of rare, inherited truncating mutations in autism","volume":"47","author":"Krumm","year":"2015","journal-title":"Nat Genet"},{"key":"2026071603352545500_B6","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1038\/s41436-021-01222-w","article-title":"Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders","volume":"23","author":"May","year":"2021","journal-title":"Genet Med"},{"key":"2026071603352545500_B7","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2019.05.020","article-title":"Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals","volume":"105","author":"Epi25 Collaborative. Electronic address, s.b.u.e.a","year":"2019","journal-title":"Am J Hum Genet"},{"key":"2026071603352545500_B8","volume-title":"Sodium Channel Mutations and Epilepsy. Jasper\u2019s Basic Mechanisms of the Epilepsies.","author":"Catterall","year":"2012.","edition":"4th ed"},{"key":"2026071603352545500_B9","doi-asserted-by":"publisher","first-page":"e568","DOI":"10.1212\/NXG.0000000000000568","article-title":"Expanding the genotypic spectrum of congenital sensory and autonomic neuropathies using whole-exome sequencing","volume":"7","author":"Palma","year":"2021","journal-title":"Neurol Genet"},{"key":"2026071603352545500_B10","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/(SICI)1098-1004(200001)15:1&lt;45::AID-HUMU10&gt;3.0.CO;2-T","article-title":"Human gene mutation database-a biomedical information and research resource","volume":"15","author":"Krawczak","year":"2000","journal-title":"Hum Mutat"},{"key":"2026071603352545500_B11","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/S2213-2600(14)70100-6","article-title":"Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial","volume":"2","author":"Kerem","year":"2014","journal-title":"Lancet Respir Med"},{"key":"2026071603352545500_B12","doi-asserted-by":"publisher","first-page":"12508","DOI":"10.1073\/pnas.1605336113","article-title":"Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression","volume":"113","author":"Roy","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026071603352545500_B13","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1146\/annurev-genom-091212-153527","article-title":"Therapeutics based on stop codon readthrough","volume":"15","author":"Keeling","year":"2014","journal-title":"Annu Rev Genom Hum Genet"},{"key":"2026071603352545500_B14","doi-asserted-by":"publisher","first-page":"e52611","DOI":"10.7554\/eLife.52611","article-title":"Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides","volume":"9","author":"Wangen","year":"2020","journal-title":"eLife"},{"key":"2026071603352545500_B15","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/362709a0","article-title":"Instability and decay of the primary structure of DNA","volume":"362","author":"Lindahl","year":"1993","journal-title":"Nature"},{"key":"2026071603352545500_B16","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/s41573-023-00829-9","article-title":"tRNA therapeutics for genetic diseases","volume":"23","author":"Coller","year":"2024","journal-title":"Nat Rev Drug Discov"},{"key":"2026071603352545500_B17","doi-asserted-by":"publisher","first-page":"7976","DOI":"10.1021\/acs.chemrev.4c00142","article-title":"Mechanisms and Delivery of tRNA Therapeutics","volume":"124","author":"Ward","year":"2024","journal-title":"Chem Rev"},{"key":"2026071603352545500_B18","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1038\/s41467-019-08329-4","article-title":"Engineered transfer RNAs for suppression of premature termination codons","volume":"10","author":"Lueck","year":"2019","journal-title":"Nat Commun"},{"key":"2026071603352545500_B19","doi-asserted-by":"publisher","first-page":"102032","DOI":"10.1016\/j.omtn.2023.102032","article-title":"Transfer RNA-mediated restoration of potassium current and electrical correction in premature termination long-QT syndrome hERG mutants","volume":"34","author":"Blomquist","year":"2023","journal-title":"Molecular Therapy Nucleic Acids"},{"key":"2026071603352545500_B20","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/j.omtn.2022.04.033","article-title":"Efficient suppression of endogenous CFTR nonsense mutations using anticodon-engineered transfer RNAs","volume":"28","author":"Ko","year":"2022","journal-title":"Mol Ther Nucleic Acids"},{"key":"2026071603352545500_B21","doi-asserted-by":"publisher","first-page":"31791","DOI":"10.1038\/s41598-024-82766-0","article-title":"Engineered tRNAs efficiently suppress CDKL5 premature termination codons","volume":"14","author":"Pezzini","year":"2024","journal-title":"Sci Rep"},{"key":"2026071603352545500_B22","doi-asserted-by":"publisher","first-page":"e00391","DOI":"10.1016\/j.neurot.2024.e00391","article-title":"Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders","volume":"21","author":"Wang","year":"2024","journal-title":"Neurotherapeutics"},{"key":"2026071603352545500_B23","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/s41586-022-04533-3","article-title":"AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice","volume":"604","author":"Wang","year":"2022","journal-title":"Nature"},{"key":"2026071603352545500_B24","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1038\/s41586-023-06133-1","article-title":"Engineered tRNAs suppress nonsense mutations in cells and in vivo","volume":"618","author":"Albers","year":"2023","journal-title":"Nature"},{"key":"2026071603352545500_B25","doi-asserted-by":"publisher","first-page":"11185","DOI":"10.1038\/s41467-025-66176-y","article-title":"AAV-delivered engineered suppressor tRNA rescues visual function in mice with an inherited retinal disease","volume":"16","author":"Ren","year":"2025","journal-title":"Nat Commun"},{"key":"2026071603352545500_B26","doi-asserted-by":"publisher","first-page":"W54","DOI":"10.1093\/nar\/gkw413","article-title":"tRNAscan-SE On-line: integrating search and context for analysis of transfer RNA genes","volume":"44","author":"Lowe","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026071603352545500_B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02982-5","article-title":"An engineered UGA suppressor tRNA gene for disease-agnostic AAV delivery","author":"Xu","year":"2026","journal-title":"Nat Biotechnol"},{"key":"2026071603352545500_B28","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/j.ymthe.2023.02.009","article-title":"A luciferase reporter mouse model to optimize in vivo gene editing validated by lipid nanoparticle delivery of adenine base editors","volume":"31","author":"Yu","year":"2023","journal-title":"Mol Ther"},{"key":"2026071603352545500_B29","doi-asserted-by":"crossref","first-page":"5775","DOI":"10.1038\/s41467-024-50161-y","article-title":"m(3)C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response","volume":"15","author":"Cui","year":"2024","journal-title":"Nat Commun"},{"key":"2026071603352545500_B30","doi-asserted-by":"publisher","first-page":"E10899","DOI":"10.1073\/pnas.1715501114","article-title":"Aminoglycoside interactions and impacts on the eukaryotic ribosome","volume":"114","author":"Prokhorova","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026071603352545500_B31","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1038\/s41467-024-47258-9","article-title":"Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations","volume":"15","author":"Bharti","year":"2024","journal-title":"Nat Commun"},{"key":"2026071603352545500_B32","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1126\/science.286.5446.1893","article-title":"Quality control mechanisms during translation","volume":"286","author":"Ibba","year":"1999","journal-title":"Science"},{"key":"2026071603352545500_B33","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1146\/annurev-biochem-071921-122857","article-title":"The structural dynamics of translation","volume":"91","author":"Korostelev","year":"2022","journal-title":"Annu Rev Biochem"},{"key":"2026071603352545500_B34","first-page":"9519","article-title":"Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse","volume":"44","author":"Depreux","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026071603352545500_B35","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1007\/s40263-021-00878-x","article-title":"Nusinersen: a review in 5q spinal muscular atrophy","volume":"35","author":"Hoy","year":"2021","journal-title":"CNS Drugs"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/13\/gkag695\/68997366\/gkag695.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/13\/gkag695\/68997366\/gkag695.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T07:35:36Z","timestamp":1784187336000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/doi\/10.1093\/nar\/gkag695\/8735594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":35,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2026,7,3]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkag695","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7,22]]},"published":{"date-parts":[[2026,7,3]]},"article-number":"gkag695"}}