{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T01:33:16Z","timestamp":1794533596747,"version":"4.9.1"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"8092","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2025,12,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Precise genome-editing technologies such as base editing\n                    <jats:sup>1,2<\/jats:sup>\n                    and prime editing\n                    <jats:sup>3<\/jats:sup>\n                    can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused by premature stop codons, suppressor tRNAs (sup-tRNAs) offer a more general strategy. Existing approaches to use sup-tRNAs therapeutically, however, require lifelong administration\n                    <jats:sup>4,5<\/jats:sup>\n                    or show modest potency, necessitating potentially toxic overexpression. Here we present prime editing-mediated readthrough of premature termination codons (PERT), a strategy to rescue nonsense mutations in a disease-agnostic manner by using prime editing to permanently convert a dispensable endogenous tRNA into an optimized sup-tRNA. Iterative screening of thousands of variants of all 418 human tRNAs identified tRNAs with the strongest sup-tRNA potential. We optimized prime editing agents to install an engineered sup-tRNA at a single genomic locus without overexpression and observed efficient readthrough of premature termination codons and protein rescue in human cell models of Batten disease, Tay\u2013Sachs disease and cystic fibrosis. In vivo delivery of a single prime editor that converts an endogenous mouse tRNA into a sup-tRNA extensively rescued disease pathology in a model of Hurler syndrome. PERT did not induce detected readthrough of natural stop codons or cause significant transcriptomic or proteomic changes. Our findings suggest the potential of disease-agnostic therapeutic genome-editing approaches that require only a single composition of matter to treat diverse genetic diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-09732-2","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T16:02:05Z","timestamp":1763568125000},"page":"191-202","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Prime editing-installed suppressor tRNAs for disease-agnostic genome editing"],"prefix":"10.1038","volume":"648","author":[{"given":"Sarah E.","family":"Pierce","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Erwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyede","family":"Oye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-8670","authenticated-orcid":false,"given":"Meirui","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4131-1855","authenticated-orcid":false,"given":"Nicholas","family":"Krasnow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9053-1336","authenticated-orcid":false,"given":"Emily","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-7308","authenticated-orcid":false,"given":"Aditya","family":"Raguram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davis","family":"Seelig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Osborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9943-7557","authenticated-orcid":false,"given":"David R.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"9732_CR1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nature24644","volume":"551","author":"NM Gaudelli","year":"2017","unstructured":"Gaudelli, N. 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After reviewing all the information and records, we confirm that the mouse identification numbers were incorrectly listed in the narrative text of the pathology report, and the study title on the signature page of the pathology report was also incorrectly listed. The authors have corrected these errors in an updated pathology report, which also includes clarification of the timing for unblinding. The mouse and pathology IDs were correct in the data tables, and the conclusions are not affected.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.E.P., S.E., K.O., A.R. and D.R.L. are inventors on a patent application filed by the Broad Institute on the design and applications of PERT. D.R.L. is a co-founder of Beam Therapeutics, Prime Medicine, Pairwise Plants, Editas Medicine and nChroma Bio, companies that use or deliver genome-editing agents. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}