{"doi":"10.1038/s41586-022-04533-3","title":"AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice","abstract":null,"journal":"Nature","year":2022,"id":600665,"datarank":0.7401710899696038,"base_score":4.9344739331306915,"endowment":4.9344739331306915,"self_citation_contribution":0.7401710899696038,"citation_network_contribution":0.0,"self_endowment_contribution":0.7401710899696038,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":138,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":285838,"name":"Yue Zhang","orcid":"0000-0003-1144-1445","position":1,"is_corresponding":false},{"id":1539997,"name":"Craig A. Mendonca","orcid":"0000-0001-9938-6481","position":2,"is_corresponding":false},{"id":272874,"name":"Onur Yukselen","orcid":null,"position":3,"is_corresponding":false},{"id":109684,"name":"Khaja Muneeruddin","orcid":"0000-0003-1371-4427","position":4,"is_corresponding":false},{"id":324689,"name":"Lingzhi Ren","orcid":null,"position":5,"is_corresponding":false},{"id":1000104,"name":"Jialing Liang","orcid":null,"position":6,"is_corresponding":false},{"id":1033523,"name":"Chen Zhou","orcid":"0000-0002-0348-7884","position":7,"is_corresponding":false},{"id":344875,"name":"Jun Xie","orcid":"0000-0001-9565-1567","position":8,"is_corresponding":false},{"id":488599,"name":"Jia Li","orcid":"0000-0003-1076-4496","position":9,"is_corresponding":false},{"id":1378446,"name":"Zhong Jiang","orcid":"0000-0002-0822-3298","position":10,"is_corresponding":false},{"id":64946,"name":"Alper Küçükural","orcid":"0000-0001-9983-394X","position":11,"is_corresponding":false},{"id":109685,"name":"Scott A. Shaffer","orcid":"0000-0002-5264-3257","position":12,"is_corresponding":false},{"id":226490,"name":"Guangping Gao","orcid":"0000-0003-0097-9012","position":13,"is_corresponding":false},{"id":226489,"name":"Dan Wang","orcid":"0000-0001-9079-2360","position":14,"is_corresponding":false},{"id":633967,"name":"Jiaming Wang","orcid":"0000-0002-4834-967X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice","abstract":"Gene therapy is a potentially curative medicine for many currently untreatable diseases, and recombinant adeno-associated virus (rAAV) is the most successful gene delivery vehicle for in vivo applications<sup>1-3</sup>. However, rAAV-based gene therapy suffers from several limitations, such as constrained DNA cargo size and toxicities caused by non-physiological expression of a transgene<sup>4-6</sup>. Here we show that rAAV delivery of a suppressor tRNA (rAAV.sup-tRNA) safely and efficiently rescued a genetic disease in a mouse model carrying a nonsense mutation, and effects lasted for more than 6 months after a single treatment. Mechanistically, this was achieved through a synergistic effect of premature stop codon readthrough and inhibition of nonsense-mediated mRNA decay. rAAV.sup-tRNA had a limited effect on global readthrough at normal stop codons and did not perturb endogenous tRNA homeostasis, as determined by ribosome profiling and tRNA sequencing, respectively. By optimizing the AAV capsid and the route of administration, therapeutic efficacy in various target tissues was achieved, including liver, heart, skeletal muscle and brain. This study demonstrates the feasibility of developing a toolbox of AAV-delivered nonsense suppressor tRNAs operating on premature termination codons (AAV-NoSTOP) to rescue pathogenic nonsense mutations and restore gene function under endogenous regulation. As nonsense mutations account for 11% of pathogenic mutations, AAV-NoSTOP can benefit a large number of patients. AAV-NoSTOP obviates the need to deliver a full-length protein-coding gene that may exceed the rAAV packaging limit, elicit adverse immune responses or cause transgene-related toxicities. It therefore represents a valuable addition to gene therapeutics.","is_dataset_classified":null,"base_score":4.9344739331306915,"endowment":4.9344739331306915,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35322228","pmcid":"PMC9446716","openalex_id":"https://openalex.org/W4220743064","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"P01 HL158506","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"U19 AI149646","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI121135","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"UG3 HL147367","title":null},{"funder_name":"NCATS NIH HHS","grant_id":"UL1 TR001453","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"P01 HL131471","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL097088","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL152723","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"P01 AI100263","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS076991","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"UH3 HL147367","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P01AI100263-03","title":"Viral escape from AAV expressed transgenes"},{"funder_name":"National Institutes of Health","grant_id":"1R01HL097088-01A2","title":"Next Generation of Recombinant AAV Serotype Vectors for Gene Therapy"},{"funder_name":"National Institutes of Health","grant_id":"1P01HL158506-01","title":"Models and Gene Therapies for AAT Deficiency"},{"funder_name":"National Institutes of Health","grant_id":"5P01HL131471-02","title":"New Approaches to Gene Therapy for Alpha-1 Antitrypsin Deficiency"},{"funder_name":"National Institutes of Health","grant_id":"6U19AI149646-03","title":"An AAV-mediated functional cure and its impact on the reservoir"},{"funder_name":"National Institutes of Health","grant_id":"5R01AI121135-05","title":"Fcgamma receptor-mediated suppression of immunodeficiency virus replication"},{"funder_name":"National Institutes of Health","grant_id":"1UL1TR001453-01","title":"University of Massachusetts Center for Clinical and Translational Science"},{"funder_name":"National Institutes of Health","grant_id":"5R01NS076991-07","title":"Novel Gene Therapy Strategies for Canavan Disease"},{"funder_name":"National Institutes of Health","grant_id":"5UG3HL147367-03","title":"Develop combinatorial non-viral and viral CRISPR delivery for lung diseases"}],"total_grants":20,"fwci":9.0099,"citation_percentile":0.9891355,"influential_citations":0,"citation_trend":[{"year":2022,"count":8},{"year":2023,"count":30},{"year":2024,"count":43},{"year":2025,"count":34},{"year":2026,"count":22}],"oa_status":"green","license":"Springer TDM","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9446716","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9446716","host_type":"repository"},{"url":"https://www.nature.com/articles/s41586-022-04533-3.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41586-022-04533-3","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41586-022-04533-3","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35322228","host_type":"repository"},{"url":"https://escholarship.umassmed.edu/bioinformatics_pubs/175","host_type":""},{"url":"https://doi.org/https://doi.org/10.1038/s41586-022-04533-3","host_type":""},{"url":"https://doi.org/https://doi.org/20.500.14038/25964","host_type":""}],"fields_of_study":["RNA Interference and Gene Delivery","Virus-based gene therapy research","RNA and protein synthesis mechanisms","Adenoviridae","Animals","Codon, Nonsense","Codon, Terminator","Dependovirus","Genetic Diseases, Inborn","Genetic Therapy","Genetic Vectors","Humans","Mice","Nonsense Mediated mRNA Decay","RNA, Transfer"],"mesh_terms":["Dependovirus","Adenoviridae","Animals","Genetic Vectors","Humans","RNA, Transfer","Genetic Therapy","Codon, Terminator","Codon, Nonsense","Genetic Diseases, Inborn","Mice","Nonsense Mediated mRNA Decay"],"keywords":["Nonsense mutation","Biology","Genetic enhancement","Adeno-associated virus","Stop codon","Gene","Transfer RNA","Transgene","Mutation","Genetics","RNA","Recombinant DNA","Vector (molecular biology)","Missense mutation","570","Genetic Vectors","Genetic Diseases, Inborn","610","Genetics and Genomics","Therapeutics","Genetic Therapy","Dependovirus","Adenoviridae","Nonsense Mediated mRNA Decay","Mice","Gene therapy","RNA, Transfer","Codon, Nonsense","Codon, Terminator","Animals","Humans","UMCCTS funding"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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