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dc.contributor.authorWang, Jiaming
dc.contributor.authorZhang, Yue
dc.contributor.authorMendonca, Craig A.
dc.contributor.authorYukselen, Onur
dc.contributor.authorMuneeruddin, Khaja
dc.contributor.authorRen, Lingzhi
dc.contributor.authorLiang, Jialing
dc.contributor.authorZhou, Chen
dc.contributor.authorXie, Jun
dc.contributor.authorLi, Jia
dc.contributor.authorJiang, Zhong
dc.contributor.authorKucukural, Alper
dc.contributor.authorShaffer, Scott A.
dc.contributor.authorGao, Guangping
dc.contributor.authorWang, Dan
dc.date2022-08-11T08:08:00.000
dc.date.accessioned2022-08-23T15:38:35Z
dc.date.available2022-08-23T15:38:35Z
dc.date.issued2022-03-23
dc.date.submitted2022-07-05
dc.identifier.citation<p>Wang J, Zhang Y, Mendonca CA, Yukselen O, Muneeruddin K, Ren L, Liang J, Zhou C, Xie J, Li J, Jiang Z, Kucukural A, Shaffer SA, Gao G, Wang D. AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice. Nature. 2022 Apr;604(7905):343-348. doi: 10.1038/s41586-022-04533-3. Epub 2022 Mar 23. PMID: 35322228. <a href="https://doi.org/10.1038/s41586-022-04533-3">Link to article on publisher's site</a></p>
dc.identifier.issn0028-0836 (Linking)
dc.identifier.doi10.1038/s41586-022-04533-3
dc.identifier.pmid35322228
dc.identifier.urihttp://hdl.handle.net/20.500.14038/25964
dc.description.abstractGene 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(1-3). 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(4-6). 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=35322228&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1038/s41586-022-04533-3
dc.subjectGene therapy
dc.subjectGenetic vectors
dc.subjectGenetics and Genomics
dc.subjectTherapeutics
dc.subjectUMCCTS funding
dc.titleAAV-delivered suppressor tRNA overcomes a nonsense mutation in mice
dc.typeJournal Article
dc.source.journaltitleNature
dc.source.volume604
dc.source.issue7905
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bioinformatics_pubs/175
dc.identifier.contextkey30064405
html.description.abstract<p>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(1-3). 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(4-6). 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.</p>
dc.identifier.submissionpathbioinformatics_pubs/175
dc.contributor.departmentRNA Therapeutics Institute
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentMass Spectrometry Facility
dc.contributor.departmentBioinformatics Core
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentHorae Gene Therapy Center
dc.source.pages343-348


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