{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:32:45Z","timestamp":1793838765052,"version":"4.6.1"},"reference-count":96,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI142756"],"award-info":[{"award-number":["U01AI142756"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute","doi-asserted-by":"publisher","award":["RM1HG009490"],"award-info":[{"award-number":["RM1HG009490"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000070","name":"U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["R01EB022376"],"award-info":[{"award-number":["R01EB022376"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM118062"],"award-info":[{"award-number":["R35GM118062"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Liu investigatorship"],"award-info":[{"award-number":["Liu investigatorship"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Biotechnol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Prime editing (PE) can make specific local changes to genomic DNA in living systems but its efficient application currently requires extensive optimization of PE guide RNA (pegRNA) sequences. Here we present OptiPrime, a machine learning model of PE efficiency based on current understanding of PE mechanisms. OptiPrime achieves state-of-the-art accuracy on PE efficiency prediction and enables prediction of nicking guide RNA (PE3) and dual pegRNA (twinPE) outcomes. We validate that OptiPrime has learned the determinants of mammalian mismatch repair (MMR) and is well suited for nominating MMR-evasive silent edits that improve PE efficiency. We demonstrate the use of OptiPrime in a variety of prospective therapeutic contexts in primary human and mouse cells. Lastly, we show that OptiPrime can be used to achieve streamlined and efficient in vivo correction of a pathogenic mutation in the brain of a mouse model of\n                    <jats:italic>KIF1A<\/jats:italic>\n                    -associated neurological disorder. We provide a webserver for OptiPrime (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/optipri.me\/\" ext-link-type=\"uri\">https:\/\/optipri.me\/<\/jats:ext-link>\n                    ) as a community resource.\n                  <\/jats:p>","DOI":"10.1038\/s41587-026-03261-7","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:02:27Z","timestamp":1786525347000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanistic machine learning for prediction of prime editing outcomes"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4034-2788","authenticated-orcid":false,"given":"Alvin","family":"Hsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1094-7180","authenticated-orcid":false,"given":"Peter J.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-465X","authenticated-orcid":false,"given":"Angus H.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin F.","family":"Hemez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2917-2060","authenticated-orcid":false,"given":"Xin D.","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Terrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2463-2155","authenticated-orcid":false,"given":"Charlie","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Selvam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Cristian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4169-0015","authenticated-orcid":false,"given":"Amber N.","family":"McElroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6444-8643","authenticated-orcid":false,"given":"Benjamin J.","family":"Steinbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3181-7262","authenticated-orcid":false,"given":"Gandhar K.","family":"Mahadeshwar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5461-5690","authenticated-orcid":false,"given":"Smriti","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1196-8669","authenticated-orcid":false,"given":"Zachary","family":"Barsdale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5261-1610","authenticated-orcid":false,"given":"Paul Z.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-1484","authenticated-orcid":false,"given":"Holt A.","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"Silverstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0597-4945","authenticated-orcid":false,"given":"Ilias","family":"Morad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan K.","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max W.","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5469-0655","authenticated-orcid":false,"given":"Benjamin P.","family":"Kleinstiver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathleen M.","family":"Lutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0957-4380","authenticated-orcid":false,"given":"Jakub","family":"Tolar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Blazar","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":[[2026,8,12]]},"reference":[{"key":"3261_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02304-3","volume":"22","author":"P Gao","year":"2021","unstructured":"Gao, P. et al. Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression. Genome Biol. 22, 83 (2021).","journal-title":"Genome Biol."},{"key":"3261_CR2","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature25164","volume":"553","author":"X Gao","year":"2018","unstructured":"Gao, X. et al. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature 553, 217\u2013221 (2018).","journal-title":"Nature"},{"key":"3261_CR3","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000940","volume":"4","author":"MH Geurts","year":"2021","unstructured":"Geurts, M. H. et al. Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids. Life Sci. Alliance 4, e202000940 (2021).","journal-title":"Life Sci. Alliance"},{"key":"3261_CR4","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.omtn.2021.06.020","volume":"25","author":"J Lin","year":"2021","unstructured":"Lin, J. et al. Modeling a cataract disorder in mice with prime editing. Mol. Ther. Nucleic Acids 25, 494\u2013501 (2021).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"3261_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-020-0165-z","volume":"6","author":"Y Liu","year":"2020","unstructured":"Liu, Y. et al. Efficient generation of mouse models with the prime editing system. Cell Discov. 6, 27 (2020).","journal-title":"Cell Discov."},{"key":"3261_CR6","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/s41586-021-03534-y","volume":"593","author":"K Musunuru","year":"2021","unstructured":"Musunuru, K. et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 593, 429\u2013434 (2021).","journal-title":"Nature"},{"key":"3261_CR7","doi-asserted-by":"publisher","first-page":"3107","DOI":"10.1016\/j.ymthe.2021.09.002","volume":"29","author":"GA Newby","year":"2021","unstructured":"Newby, G. A. & Liu, D. R. In vivo somatic cell base editing and prime editing. Mol. Therapy 29, 3107\u20133124 (2021).","journal-title":"Mol. Therapy"},{"key":"3261_CR8","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02389-w","volume":"22","author":"S-J Park","year":"2021","unstructured":"Park, S.-J. et al. Targeted mutagenesis in mouse cells and embryos using an enhanced prime editor. Genome Biol. 22, 170 (2021).","journal-title":"Genome Biol."},{"key":"3261_CR9","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/s41587-021-00933-4","volume":"39","author":"T Rothgangl","year":"2021","unstructured":"Rothgangl, T. et al. In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels. Nat. Biotechnol. 39, 949\u2013957 (2021).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19136-7","volume":"11","author":"IF Schene","year":"2020","unstructured":"Schene, I. F. et al. Prime editing for functional repair in patient-derived disease models. Nat. Commun. 11, 5352 (2020).","journal-title":"Nat. Commun."},{"key":"3261_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01234-1","volume":"8","author":"K She","year":"2023","unstructured":"She, K. et al. Dual-AAV split prime editor corrects the mutation and phenotype in mice with inherited retinal degeneration. Signal Transduct. Target. Ther. 8, 57 (2023).","journal-title":"Signal Transduct. Target. Ther."},{"key":"3261_CR12","doi-asserted-by":"crossref","unstructured":"Sousa, A. A. et al. Systematic optimization of prime editing for the efficient functional correction of CFTR F508del in human airway epithelial cells. Nat. Biomed. Eng. 9, 7\u201321 (2025).","DOI":"10.1038\/s41551-024-01233-3"},{"key":"3261_CR13","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s41551-023-01026-0","volume":"7","author":"KA Everette","year":"2023","unstructured":"Everette, K. A. et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nat. Biomed. Eng. 7, 616\u2013628 (2023).","journal-title":"Nat. Biomed. Eng."},{"key":"3261_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04580-3","volume":"9","author":"W-H Yeh","year":"2018","unstructured":"Yeh, W.-H., Chiang, H., Rees, H. A., Edge, A. S. B. & Liu, D. R. In vivo base editing of post-mitotic sensory cells. Nat. Commun. 9, 2184 (2018).","journal-title":"Nat. Commun."},{"key":"3261_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33533-5","volume":"9","author":"HK Lee","year":"2019","unstructured":"Lee, H. K. et al. Simultaneous targeting of linked loci in mouse embryos using base editing. Sci. Rep. 9, 1662 (2019).","journal-title":"Sci. Rep."},{"key":"3261_CR16","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.jid.2019.07.701","volume":"140","author":"MJ Osborn","year":"2020","unstructured":"Osborn, M. J. et al. Base editor correction of COL7A1 in recessive dystrophic epidermolysis bullosa patient-derived fibroblasts and iPSCs. J. Invest. Dermatol. 140, 338\u2013347 (2020).","journal-title":"J. Invest. Dermatol."},{"key":"3261_CR17","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/s41551-019-0357-8","volume":"4","author":"C-Q Song","year":"2020","unstructured":"Song, C.-Q. et al. Adenine base editing in an adult mouse model of tyrosinaemia. Nat. Biomed. Eng. 4, 125\u2013130 (2020).","journal-title":"Nat. Biomed. Eng."},{"key":"3261_CR18","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay9101","volume":"12","author":"W-H Yeh","year":"2020","unstructured":"Yeh, W.-H. et al. In vivo base editing restores sensory transduction and transiently improves auditory function in a mouse model of recessive deafness. Sci. Transl. Med. 12, eaay9101 (2020).","journal-title":"Sci. Transl. Med."},{"key":"3261_CR19","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1016\/j.cell.2021.01.012","volume":"184","author":"RE Hanna","year":"2021","unstructured":"Hanna, R. E. et al. Massively parallel assessment of human variants with base editor screens. Cell 184, 1064\u20131080 (2021).","journal-title":"Cell"},{"key":"3261_CR20","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/s41586-020-03086-7","volume":"589","author":"LW Koblan","year":"2021","unstructured":"Koblan, L. W. et al. In vivo base editing rescues Hutchinson\u2013Gilford progeria syndrome in mice. Nature 589, 608\u2013614 (2021).","journal-title":"Nature"},{"key":"3261_CR21","doi-asserted-by":"publisher","first-page":"10558","DOI":"10.1093\/nar\/gkab788","volume":"49","author":"S Krishnamurthy","year":"2021","unstructured":"Krishnamurthy, S. et al. Functional correction of CFTR mutations in human airway epithelial cells using adenine base editors. Nucleic Acids Res. 49, 10558\u201310572 (2021).","journal-title":"Nucleic Acids Res."},{"key":"3261_CR22","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/s41586-021-03609-w","volume":"595","author":"GA Newby","year":"2021","unstructured":"Newby, G. A. et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature 595, 295\u2013302 (2021).","journal-title":"Nature"},{"key":"3261_CR23","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41551-020-00632-6","volume":"5","author":"S Suh","year":"2021","unstructured":"Suh, S. et al. Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing. Nat. Biomed. Eng. 5, 169\u2013178 (2021).","journal-title":"Nat. Biomed. Eng."},{"key":"3261_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29490-3","volume":"13","author":"EH Choi","year":"2022","unstructured":"Choi, E. H. et al. In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration. Nat. Commun. 13, 1830 (2022).","journal-title":"Nat. Commun."},{"key":"3261_CR25","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.ymthe.2021.10.026","volume":"30","author":"F Knipping","year":"2022","unstructured":"Knipping, F. et al. Disruption of HIV-1 coreceptors CCR5 and CXCR4 in primary human T cells and hematopoietic stem and progenitor cells using base editing. Mol. Ther. 30, 130\u2013144 (2022).","journal-title":"Mol. Ther."},{"key":"3261_CR26","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/s41588-022-01056-5","volume":"54","author":"K Mouri","year":"2022","unstructured":"Mouri, K. et al. Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells. Nat. Genet. 54, 603\u2013612 (2022).","journal-title":"Nat. Genet."},{"key":"3261_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-24184-8","volume":"12","author":"A Sheriff","year":"2022","unstructured":"Sheriff, A. et al. ABE8e adenine base editor precisely and efficiently corrects a recurrent COL7A1 nonsense mutation. Sci. Rep. 12, 19643 (2022).","journal-title":"Sci. Rep."},{"key":"3261_CR28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2210104119","volume":"119","author":"S Suh","year":"2022","unstructured":"Suh, S., Choi, E. H., Raguram, A., Liu, D. R. & Palczewski, K. Precision genome editing in the eye. Proc. Natl Acad. Sci. USA 119, e2210104119 (2022).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3261_CR29","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg6518","volume":"380","author":"M Arbab","year":"2023","unstructured":"Arbab, M. et al. Base editing rescue of spinal muscular atrophy in cells and in mice. Science 380, eadg6518 (2023).","journal-title":"Science"},{"key":"3261_CR30","doi-asserted-by":"publisher","first-page":"1271813","DOI":"10.3389\/fgeed.2023.1271813","volume":"5","author":"AL Cooney","year":"2023","unstructured":"Cooney, A. L. et al. Reciprocal mutations of lung-tropic AAV capsids lead to improved transduction properties. Front. Genome Ed. 5, 1271813 (2023).","journal-title":"Front. Genome Ed."},{"key":"3261_CR31","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.omtn.2023.06.020","volume":"33","author":"AT Joynt","year":"2023","unstructured":"Joynt, A. T. et al. Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells. Mol. Ther. Nucleic Acids 33, 335\u2013350 (2023).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"3261_CR32","doi-asserted-by":"crossref","unstructured":"Kabra, M. et al. Nonviral base editing of KCNJ13 mutation preserves vision in a model of inherited retinal channelopathy. J. Clin. Invest. 133, e171356 (2023).","DOI":"10.1172\/JCI171356"},{"key":"3261_CR33","first-page":"2085","volume":"141","author":"C Li","year":"2023","unstructured":"Li, C. et al. In vivo HSC prime editing rescues sickle cell disease in a mouse model. Blood 141, 2085\u20132099 (2023).","journal-title":"Blood"},{"key":"3261_CR34","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1038\/s41589-023-01428-w","volume":"19","author":"H Li","year":"2023","unstructured":"Li, H. et al. Assigning functionality to cysteines by base editing of cancer dependency genes. Nat. Chem. Biol. 19, 1320\u20131330 (2023).","journal-title":"Nat. Chem. Biol."},{"key":"3261_CR35","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.1016\/j.cell.2023.03.035","volume":"186","author":"JD Martin-Rufino","year":"2023","unstructured":"Martin-Rufino, J. D. et al. Massively parallel base editing to map variant effects in human hematopoiesis. Cell 186, 2456\u20132474 (2023).","journal-title":"Cell"},{"key":"3261_CR36","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/s41588-023-01434-7","volume":"55","author":"T Mayuranathan","year":"2023","unstructured":"Mayuranathan, T. et al. Potent and uniform fetal hemoglobin induction via base editing. Nat. Genet. 55, 1210\u20131220 (2023).","journal-title":"Nat. Genet."},{"key":"3261_CR37","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1016\/j.cell.2023.02.027","volume":"186","author":"GE McAuley","year":"2023","unstructured":"McAuley, G. E. et al. Human T cell generation is restored in CD3\u03b4 severe combined immunodeficiency through adenine base editing. Cell 186, 1398\u20131416 (2023).","journal-title":"Cell"},{"key":"3261_CR38","doi-asserted-by":"publisher","first-page":"2439","DOI":"10.1016\/j.ymthe.2023.06.007","volume":"31","author":"CW Peters","year":"2023","unstructured":"Peters, C. W. et al. Rescue of hearing by adenine base editing in a humanized mouse model of Usher syndrome type 1F. Mol. Ther. 31, 2439\u20132453 (2023).","journal-title":"Mol. Ther."},{"key":"3261_CR39","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41591-022-02190-7","volume":"29","author":"D Reichart","year":"2023","unstructured":"Reichart, D. et al. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nat. Med. 29, 412\u2013421 (2023).","journal-title":"Nat. Med."},{"key":"3261_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40476-7","volume":"14","author":"Y Tao","year":"2023","unstructured":"Tao, Y. et al. Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR\u2013Cas9 ribonucleoprotein delivery in vivo. Nat. Commun. 14, 4928 (2023).","journal-title":"Nat. Commun."},{"key":"3261_CR41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2416827121","volume":"121","author":"SW Du","year":"2024","unstructured":"Du, S. W. et al. In vivo photoreceptor base editing ameliorates rhodopsin-E150K autosomal-recessive retinitis pigmentosa in mice. Proc. Natl Acad. Sci. USA 121, e2416827121 (2024).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"3261_CR42","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/s41587-023-01783-y","volume":"42","author":"ZA Ely","year":"2024","unstructured":"Ely, Z. A. et al. A prime editor mouse to model a broad spectrum of somatic mutations in vivo. Nat. Biotechnol. 42, 424\u2013436 (2024).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR43","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1038\/s41587-024-02172-9","volume":"43","author":"SI Gould","year":"2025","unstructured":"Gould, S. I. et al. High-throughput evaluation of genetic variants with prime editing sensor libraries. Nat. Biotechnol. 43, 1648\u20131662 (2025).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR44","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1038\/s41592-024-02256-z","volume":"21","author":"PH Kennedy","year":"2024","unstructured":"Kennedy, P. H. et al. Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput. Nat. Methods 21, 1033\u20131043 (2024).","journal-title":"Nat. Methods"},{"key":"3261_CR45","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.1016\/j.ymthe.2024.10.018","volume":"32","author":"C Li","year":"2024","unstructured":"Li, C. et al. Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice. Mol. Ther. 32, 4353\u20134371 (2024).","journal-title":"Mol. Ther."},{"key":"3261_CR46","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/s41586-023-06835-6","volume":"625","author":"R Schmidt","year":"2024","unstructured":"Schmidt, R. et al. Base-editing mutagenesis maps alleles to tune human T cell functions. Nature 625, 805\u2013812 (2024).","journal-title":"Nature"},{"key":"3261_CR47","doi-asserted-by":"publisher","first-page":"4275","DOI":"10.1016\/j.cell.2025.06.038","volume":"188","author":"AA Sousa","year":"2025","unstructured":"Sousa, A. A. et al. In vivo prime editing rescues alternating hemiplegia of childhood in mice. Cell 188, 4275\u20134294 (2025).","journal-title":"Cell"},{"key":"3261_CR48","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1056\/NEJMoa2504747","volume":"392","author":"K Musunuru","year":"2025","unstructured":"Musunuru, K. et al. Patient-specific in vivo gene editing to treat a rare genetic disease. N. Engl. J. Med. 392, 2235\u20132243 (2025).","journal-title":"N. Engl. J. Med."},{"key":"3261_CR49","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/s41586-019-1711-4","volume":"576","author":"AV Anzalone","year":"2019","unstructured":"Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149\u2013157 (2019).","journal-title":"Nature"},{"key":"3261_CR50","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1056\/NEJMoa2509807","volume":"394","author":"JL Gori","year":"2026","unstructured":"Gori, J. L. et al. Prime editing for p47phox-deficient chronic granulomatous disease. N. Engl. J. Med. 394, 1195\u20131203 (2026).","journal-title":"N. Engl. J. Med."},{"key":"3261_CR51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21337-7","volume":"12","author":"JY Hsu","year":"2021","unstructured":"Hsu, J. Y. et al. PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nat. Commun. 12, 1034 (2021).","journal-title":"Nat. Commun."},{"key":"3261_CR52","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1038\/s41596-022-00724-4","volume":"17","author":"JL Doman","year":"2022","unstructured":"Doman, J. L., Sousa, A. A., Randolph, P. B., Chen, P. J. & Liu, D. R. Designing and executing prime editing experiments in mammalian cells. Nat. Protoc. 17, 2431\u20132468 (2022).","journal-title":"Nat. Protoc."},{"key":"3261_CR53","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/s41576-022-00541-1","volume":"24","author":"PJ Chen","year":"2023","unstructured":"Chen, P. J. & Liu, D. R. Prime editing for precise and highly versatile genome manipulation. Nat. Rev. Genet. 24, 161\u2013177 (2023).","journal-title":"Nat. Rev. Genet."},{"key":"3261_CR54","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1038\/s41587-022-01613-7","volume":"41","author":"N Mathis","year":"2023","unstructured":"Mathis, N. et al. Predicting prime editing efficiency and product purity by deep learning. Nat. Biotechnol. 41, 1151\u20131159 (2023).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR55","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1016\/j.cell.2023.03.034","volume":"186","author":"G Yu","year":"2023","unstructured":"Yu, G. et al. Prediction of efficiencies for diverse prime editing systems in multiple cell types. Cell 186, 2256\u20132272 (2023).","journal-title":"Cell"},{"key":"3261_CR56","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/s41587-024-02268-2","volume":"43","author":"N Mathis","year":"2025","unstructured":"Mathis, N. et al. Machine learning prediction of prime editing efficiency across diverse chromatin contexts. Nat. Biotechnol. 43, 712\u2013719 (2025).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR57","doi-asserted-by":"publisher","first-page":"5635","DOI":"10.1016\/j.cell.2021.09.018","volume":"184","author":"PJ Chen","year":"2021","unstructured":"Chen, P. J. et al. Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Cell 184, 5635\u20135652 (2021).","journal-title":"Cell"},{"key":"3261_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28442-1","volume":"13","author":"J Ferreira da Silva","year":"2022","unstructured":"Ferreira da Silva, J. et al. Prime editing efficiency and fidelity are enhanced in the absence of mismatch repair. Nat. Commun. 13, 760 (2022).","journal-title":"Nat. Commun."},{"key":"3261_CR59","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/s41587-020-0677-y","volume":"39","author":"HK Kim","year":"2021","unstructured":"Kim, H. K. et al. Predicting the efficiency of prime editing guide RNAs in human cells. Nat. Biotechnol. 39, 198\u2013206 (2021).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR60","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1038\/s42256-023-00739-w","volume":"5","author":"F Liu","year":"2023","unstructured":"Liu, F. et al. Design of prime-editing guide RNAs with deep transfer learning. Nat. Mach. Intell. 5, 1261\u20131274 (2023).","journal-title":"Nat. Mach. Intell."},{"key":"3261_CR61","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41587-021-01133-w","volume":"40","author":"AV Anzalone","year":"2022","unstructured":"Anzalone, A. V. et al. Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing. Nat. Biotechnol. 40, 731\u2013740 (2022).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR62","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/0959-437X(95)80055-7","volume":"5","author":"R Fishel","year":"1995","unstructured":"Fishel, R. & Kolodner, R. D. Identification of mismatch repair genes and their role in the development of cancer. Curr. Opin. Genet. Dev. 5, 382\u2013395 (1995).","journal-title":"Curr. Opin. Genet. Dev."},{"key":"3261_CR63","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.molcel.2007.04.018","volume":"26","author":"JJ Warren","year":"2007","unstructured":"Warren, J. J. et al. Structure of the human MutS\u03b1 DNA lesion recognition complex. Mol. Cell 26, 579\u2013592 (2007).","journal-title":"Mol. Cell"},{"key":"3261_CR64","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/nsmb.2175","volume":"19","author":"S Gupta","year":"2012","unstructured":"Gupta, S., Gellert, M. & Yang, W. Mechanism of mismatch recognition revealed by human MutS\u03b2 bound to unpaired DNA loops. Nat. Struct. Mol. Biol. 19, 72\u201378 (2012).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"3261_CR65","doi-asserted-by":"publisher","first-page":"D862","DOI":"10.1093\/nar\/gkv1222","volume":"44","author":"MJ Landrum","year":"2015","unstructured":"Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862\u2013D868 (2015).","journal-title":"Nucleic Acids Res."},{"key":"3261_CR66","doi-asserted-by":"publisher","first-page":"3744","DOI":"10.1016\/S0021-9258(19)67858-0","volume":"266","author":"DC Thomas","year":"1991","unstructured":"Thomas, D. C., Roberts, J. D. & Kunkel, T. A. Heteroduplex repair in extracts of human HeLa cells. J. Biol. Chem. 266, 3744\u20133751 (1991).","journal-title":"J. Biol. Chem."},{"key":"3261_CR67","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1126\/science.aaw4741","volume":"367","author":"M Raissi","year":"2020","unstructured":"Raissi, M., Yazdani, A. & Karniadakis, G. E. Hidden fluid mechanics: learning velocity and pressure fields from flow visualizations. Science 367, 1026\u20131030 (2020).","journal-title":"Science"},{"key":"3261_CR68","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq3745","volume":"8","author":"Z Chen","year":"2022","unstructured":"Chen, Z., King, W. C., Hwang, A., Gerstein, M. & Zhang, J. DeepVelo: single-cell transcriptomic deep velocity field learning with neural ordinary differential equations. Sci. Adv. 8, eabq3745 (2022).","journal-title":"Sci. Adv."},{"key":"3261_CR69","unstructured":"Chen, R. T. Q., Rubanova, Y., Bettencourt, J. & Duvenaud, D. Neural ordinary differential equations. In Proc. 32nd International Conference on Neural Information Processing Systems https:\/\/proceedings.neurips.cc\/paper_files\/paper\/2018\/file\/69386f6bb1dfed68692a24c8686939b9-Paper.pdf (2018)."},{"key":"3261_CR70","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/wsbm.165","volume":"4","author":"DC Resasco","year":"2012","unstructured":"Resasco, D. C. et al. Virtual Cell: computational tools for modeling in cell biology. Wiley Interdiscip. Rev. Syst. Biol. Med. 4, 129\u2013140 (2012).","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"3261_CR71","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/S0006-3495(97)78146-3","volume":"73","author":"J Schaff","year":"1997","unstructured":"Schaff, J., Fink, C. C., Slepchenko, B., Carson, J. H. & Loew, L. M. A general computational framework for modeling cellular structure and function. Biophys. J. 73, 1135\u20131146 (1997).","journal-title":"Biophys. J."},{"key":"3261_CR72","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","volume":"596","author":"J Jumper","year":"2021","unstructured":"Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583\u2013589 (2021).","journal-title":"Nature"},{"key":"3261_CR73","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493\u2013500 (2024).","journal-title":"Nature"},{"key":"3261_CR74","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33024-2","volume":"13","author":"PC DeWeirdt","year":"2022","unstructured":"DeWeirdt, P. C. et al. Accounting for small variations in the tracrRNA sequence improves sgRNA activity predictions for CRISPR screening. Nat. Commun. 13, 5255 (2022).","journal-title":"Nat. Commun."},{"key":"3261_CR75","doi-asserted-by":"crossref","unstructured":"Kim, H. K. et al. SpCas9 activity prediction by DeepSpCas9, a deep learning-based model with high generalization performance. Sci. Adv. 5, eaax9249 (2019).","DOI":"10.1126\/sciadv.aax9249"},{"key":"3261_CR76","unstructured":"Scott, M. & Lundberg, S.-I. L. A unified approach to interpreting model predictions. In Proc. 31st International Conference on Neural Information Processing Systems (eds von Luxburg, U., Guyon, I., Bengio, S., Wallach, H. & Fergus, R.) 4768\u20134777 (Curran Associates, 2017)."},{"key":"3261_CR77","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41551-024-01227-1","volume":"9","author":"S Pandey","year":"2025","unstructured":"Pandey, S. et al. Efficient site-specific integration of large genes in mammalian cells via continuously evolved recombinases and prime editing. Nat. Biomed. Eng. 9, 22\u201339 (2025).","journal-title":"Nat. Biomed. Eng."},{"key":"3261_CR78","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1093\/nar\/29.1.308","volume":"29","author":"ST Sherry","year":"2001","unstructured":"Sherry, S. T. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29, 308\u2013311 (2001).","journal-title":"Nucleic Acids Res."},{"key":"3261_CR79","doi-asserted-by":"publisher","first-page":"D1243","DOI":"10.1093\/nar\/gkae974","volume":"53","author":"G Perez","year":"2025","unstructured":"Perez, G. et al. The UCSC Genome Browser database: 2025 update. Nucleic Acids Res. 53, D1243\u2013D1249 (2025).","journal-title":"Nucleic Acids Res."},{"key":"3261_CR80","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1038\/s41596-020-00465-2","volume":"16","author":"RT Walton","year":"2021","unstructured":"Walton, R. T., Hsu, J. Y., Joung, J. K. & Kleinstiver, B. P. Scalable characterization of the PAM requirements of CRISPR\u2013Cas enzymes using HT-PAMDA. Nat. Protoc. 16, 1511\u20131547 (2021).","journal-title":"Nat. Protoc."},{"key":"3261_CR81","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1126\/science.aba8853","volume":"368","author":"RT Walton","year":"2020","unstructured":"Walton, R. T., Christie, K. A., Whittaker, M. N. & Kleinstiver, B. P. Unconstrained genome targeting with near-PAMless engineered CRISPR\u2013Cas9 variants. Science 368, 290\u2013296 (2020).","journal-title":"Science"},{"key":"3261_CR82","unstructured":"Marshall, B. Patient registry annual data report. Cystic Fibrosis Foundation https:\/\/www.cff.org\/media\/31216\/download (2022)."},{"key":"3261_CR83","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nature16526","volume":"529","author":"BP Kleinstiver","year":"2016","unstructured":"Kleinstiver, B. P. et al. High-fidelity CRISPR\u2013Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529, 490\u2013495 (2016).","journal-title":"Nature"},{"key":"3261_CR84","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.matbio.2018.04.001","volume":"71-72","author":"C Has","year":"2018","unstructured":"Has, C., Nystr\u00f6m, A., Saeidian, A. H., Bruckner-Tuderman, L. & Uitto, J. Epidermolysis bullosa: molecular pathology of connective tissue components in the cutaneous basement membrane zone. Matrix Biol. 71-72, 313\u2013329 (2018).","journal-title":"Matrix Biol."},{"key":"3261_CR85","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1126\/science.aar3246","volume":"359","author":"JT Sockolosky","year":"2018","unstructured":"Sockolosky, J. T. et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science 359, 1037\u20131042 (2018).","journal-title":"Science"},{"key":"3261_CR86","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nbt.3437","volume":"34","author":"JG Doench","year":"2016","unstructured":"Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR\u2013Cas9. Nat. Biotechnol. 34, 184\u2013191 (2016).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR87","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07901-8","volume":"9","author":"KR Sanson","year":"2018","unstructured":"Sanson, K. R. et al. Optimized libraries for CRISPR\u2013Cas9 genetic screens with multiple modalities. Nat. Commun. 9, 5416 (2018).","journal-title":"Nat. Commun."},{"key":"3261_CR88","doi-asserted-by":"publisher","first-page":"3103","DOI":"10.1016\/j.ymthe.2021.10.019","volume":"29","author":"FD Urnov","year":"2021","unstructured":"Urnov, F. D. Imagine CRISPR cures. Mol. Ther. 29, 3103\u20133106 (2021).","journal-title":"Mol. Ther."},{"key":"3261_CR89","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1002\/acn3.198","volume":"2","author":"S Esmaeeli Nieh","year":"2015","unstructured":"Esmaeeli Nieh, S. et al. De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Ann. Clin. Transl. Neurol. 2, 623\u2013635 (2015).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"3261_CR90","doi-asserted-by":"publisher","first-page":"3983","DOI":"10.1016\/j.cell.2023.07.039","volume":"186","author":"JL Doman","year":"2023","unstructured":"Doman, J. L. et al. Phage-assisted evolution and protein engineering yield compact, efficient prime editors. Cell 186, 3983\u20134002 (2023).","journal-title":"Cell"},{"key":"3261_CR91","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/s41587-023-01758-z","volume":"42","author":"JR Davis","year":"2024","unstructured":"Davis, J. R. et al. Efficient prime editing in mouse brain, liver and heart with dual AAVs. Nat. Biotechnol. 42, 253\u2013264 (2024).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR92","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/s41588-024-02053-6","volume":"57","author":"J Linder","year":"2025","unstructured":"Linder, J., Srivastava, D., Yuan, H., Agarwal, V. & Kelley, D. R. Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation. Nat. Genet. 57, 949\u2013961 (2025).","journal-title":"Nat. Genet."},{"key":"3261_CR93","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1038\/s41586-025-10014-0","volume":"649","author":"Z Avsec","year":"2026","unstructured":"Avsec, Z. et al. Advancing regulatory variant effect prediction with AlphaGenome. Nature 649, 1206\u20131218 (2026).","journal-title":"Nature"},{"key":"3261_CR94","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan, K. et al. Predicting splicing from primary sequence with deep learning. Cell 176, 535\u2013548 (2019).","journal-title":"Cell"},{"key":"3261_CR95","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/s41587-019-0032-3","volume":"37","author":"K Clement","year":"2019","unstructured":"Clement, K. et al. CRISPResso2 provides accurate and rapid genome editing sequence analysis. Nat. Biotechnol. 37, 224\u2013226 (2019).","journal-title":"Nat. Biotechnol."},{"key":"3261_CR96","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1037\/0033-2909.87.2.245","volume":"87","author":"JH Steiger","year":"1980","unstructured":"Steiger, J. H. Tests for comparing elements of a correlation matrix. Psychol. Bull. 87, 245\u2013251 (1980).","journal-title":"Psychol. Bull."}],"container-title":["Nature Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41587-026-03261-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41587-026-03261-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41587-026-03261-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:02:34Z","timestamp":1786525354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41587-026-03261-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":96,"alternative-id":["3261"],"URL":"https:\/\/doi.org\/10.1038\/s41587-026-03261-7","relation":{},"ISSN":["1087-0156","1546-1696"],"issn-type":[{"value":"1087-0156","type":"print"},{"value":"1546-1696","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"assertion":[{"value":"14 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.H., P.J.C. and D.R.L. have filed patent applications on aspects of this work. A.H. is currently an employee at Biohub. P.J.C. is currently an employee at Jefferies. C.F.H. is currently an employee at the CF Foundation. X.D.G. currently holds an academic appointment at the University of Pittsburgh. S.P. is currently an employee at CRISPR Therapeutics. R.K.K. is currently an employee at Google Deepmind. M.W.S. is currently an employee at Genentech. D.R.L. is a consultant and\/or equity holder of Prime Medicine, Beam Therapeutics, Pairwise Plants and nChroma Bio, companies that use and\/or deliver gene-editing or genome-engineering technologies. R.A.S. and B.P.K. are inventors on patent applications filed by Mass General Brigham that describe genome-engineering technologies. B.P.K. is a consultant for EcoR1 capital, Novartis Venture Fund and Jumble Therapeutics and is on the scientific advisory boards of Acrigen Biosciences, Life Edit Therapeutics and Prime Medicine. B.P.K. has a financial interest in Prime Medicine, a company developing therapeutic CRISPR\u2013Cas technologies for gene editing. B.P.K.\u2018s interests were reviewed and are managed by Mass General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. M.J.O. receives compensation as a consultant for Agathos Biologics. B.R.B. reports research funding from BlueRock Therapeutics and Carisma Therapeutics and consulting fees from BlueRock Therapeutics, Editas Medicine, Janssen Oncology, Sandoz, Legend Biotech, GentiBio and Magenta Therapeutics. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}