{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:16:28Z","timestamp":1778696188814,"version":"3.51.4"},"reference-count":60,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"849","funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_185293"],"award-info":[{"award-number":["310030_185293"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["320030_207965"],"award-info":[{"award-number":["320030_207965"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020026","name":"Citrin Foundation","doi-asserted-by":"publisher","award":["RG24003"],"award-info":[{"award-number":["RG24003"]}],"id":[{"id":"10.13039\/501100020026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020026","name":"Citrin Foundation","doi-asserted-by":"publisher","award":["RG24003"],"award-info":[{"award-number":["RG24003"]}],"id":[{"id":"10.13039\/501100020026","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Research Priority Programs","award":["\u2018ITINERARE\u2019"],"award-info":[{"award-number":["\u2018ITINERARE\u2019"]}]},{"name":"University Research Priority Programs","award":["\u2018ITINERARE\u2019"],"award-info":[{"award-number":["\u2018ITINERARE\u2019"]}]},{"name":"University Research Priority Programs","award":["\u2018ITINERARE\u2019"],"award-info":[{"award-number":["\u2018ITINERARE\u2019"]}]},{"name":"University Research Priority Programs","award":["\u2018ITINERARE\u2019"],"award-info":[{"award-number":["\u2018ITINERARE\u2019"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,5,13]]},"abstract":"<jats:p>\n                    Citrullinemia type I (CTLN1) is a severe urea cycle disorder caused by pathogenic variants in the\n                    <jats:italic toggle=\"yes\">ASS1<\/jats:italic>\n                    (argininosuccinate synthetase 1) gene, for which liver transplantation remains the only curative option. Here, we used prime editing to correct the\n                    <jats:italic toggle=\"yes\">\n                      Ass1\n                      <jats:sup>fold<\/jats:sup>\n                    <\/jats:italic>\n                    mouse model of CTLN1. Adeno-associated virus (AAV)\u2013mediated delivery of the PE7 prime editor with an optimized prime editing guide RNA (pegRNA) achieved 71 and 54% correction of the pathogenic\n                    <jats:italic toggle=\"yes\">Ass1<\/jats:italic>\n                    mutation in hepatocytes of neonates and juveniles, respectively. Delivery of mRNA-encoded PE7 and synthetic pegRNA via lipid nanoparticles (LNPs) resulted in 24% correction after a single 3 mg kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    dose in neonates and 13% after three 4 mg kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    doses in juveniles. All treated groups showed full normalization of survival and of blood citrulline and ammonia concentrations, with restored urea cycle function and correction of natural behavior defects. Consistent with these findings, immunostaining demonstrated restoration of wild-type\u2013like ASS1 protein localization in functionally relevant periportal and intermediate-zone hepatocytes. Editing was confined to the liver, with minimal indel formation and off-target activity and only transient elevations in liver enzymes. In a cellular reporter system, 6 of 15 recurrent human pathogenic\n                    <jats:italic toggle=\"yes\">ASS1<\/jats:italic>\n                    mutations studied, including the most common\n                    <jats:italic toggle=\"yes\">\n                      ASS1\n                      <jats:sup>G390R<\/jats:sup>\n                    <\/jats:italic>\n                    variant, were corrected with similar or higher efficiencies than\n                    <jats:italic toggle=\"yes\">\n                      Ass1\n                      <jats:sup>fold<\/jats:sup>\n                    <\/jats:italic>\n                    . These findings highlight prime editing as a precise and potentially curative treatment strategy for individuals with CTLN1 and other genetic liver diseases.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aec7274","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:58:22Z","timestamp":1778695102000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["RNA-LNP\u2013mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0851-8333","authenticated-orcid":true,"given":"Andr\u00e1s","family":"T\u00e1las","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora I.","family":"Ioannidi","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0914-8541","authenticated-orcid":true,"given":"Yanik","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6285-2602","authenticated-orcid":true,"given":"Tatjana","family":"Haenggi","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9ter Istv\u00e1n","family":"Kulcs\u00e1r","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Z\u00fcrcher","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5589-5798","authenticated-orcid":true,"given":"Erica","family":"Faccin","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1395-823X","authenticated-orcid":true,"given":"Woohyun J.","family":"Moon","sequence":"additional","affiliation":[{"name":"Acuitas Therapeutics Inc., Vancouver, BC, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-0695","authenticated-orcid":true,"given":"Lucas","family":"Kissling","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3454-9045","authenticated-orcid":true,"given":"Elina Andrea","family":"Villiger","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5693-461X","authenticated-orcid":true,"given":"Mai","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Rothgangl","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharan","family":"Janjuha","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9310-1366","authenticated-orcid":true,"given":"Paulo J. C.","family":"Lin","sequence":"additional","affiliation":[{"name":"Acuitas Therapeutics Inc., Vancouver, BC, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4426-314X","authenticated-orcid":true,"given":"Martin","family":"Poms","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Biochemistry, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-1493","authenticated-orcid":true,"given":"Hiromi","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9028-987X","authenticated-orcid":true,"given":"M\u00e1t\u00e9","family":"Vadovics","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4365-2119","authenticated-orcid":true,"given":"Andreas","family":"Reichmuth","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0628-7140","authenticated-orcid":true,"given":"Manfred","family":"Kopf","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1008-6242","authenticated-orcid":true,"given":"Norbert","family":"Pardi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-5251","authenticated-orcid":true,"given":"Ying K.","family":"Tam","sequence":"additional","affiliation":[{"name":"Acuitas Therapeutics Inc., Vancouver, BC, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0635-091X","authenticated-orcid":true,"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children\u2019s Research Center, University Children\u2019s Hospital Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0767-2953","authenticated-orcid":true,"given":"Gerald","family":"Schwank","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-019-0614-4"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12100"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0686-6"},{"key":"e_1_3_2_5_2","unstructured":"S. C. Quinonez K. N. Lee \u201cCitrullinemia type I\u201d in GeneReviews (University of Washington 2022); https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1458\/."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2003.08.002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-025-00719-0"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.139"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2013.53"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232314940"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.12.024"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1906182116"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2023.06.023"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-023-00585-7"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033286"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1080\/17435889.2024.2406218"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00697-6"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cobme.2023.100478"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17946"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24644"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1711-4"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10230"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20847"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100118"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01613-7"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02268-2"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01039-7"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.018"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39137-6"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01133-w"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07259-6"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-025-01399-4"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-10-534032"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0209-1"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3117"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2022.138"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23184"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28442-1"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003632"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6890-14-18"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03534-y"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2504747"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.12.028"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.181760"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.02.022"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1039\/D4MD00652F"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-58653-1"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsb2512695"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adc9937"},{"key":"e_1_3_2_50_2","doi-asserted-by":"crossref","unstructured":"M. Vadovics H. Muramatsu A. S\u00e1rk\u00f6zy N. Pardi \u201cProduction and evaluation of nucleoside-modified mRNA vaccines for infectious diseases\u201d in RNA Vaccines: Methods and Protocols (Springer 2024) pp. 167\u2013181.","DOI":"10.1007\/978-1-0716-3770-8_7"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.02.018"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.03.003"},{"key":"e_1_3_2_53_2","unstructured":"X. Du S. M. Ansell Lipids and lipid nanoparticle formulations for delivery of nucleic acids. WO 2017\/004143 (2017)."},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2016.11.038"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44324-025-00051-8"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26461-y"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0032-3"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15021-5"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3534"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-025-01512-7"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-021-04344-9"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.aec7274","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:58:42Z","timestamp":1778695122000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.aec7274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":60,"journal-issue":{"issue":"849","published-print":{"date-parts":[[2026,5,13]]}},"alternative-id":["10.1126\/scitranslmed.aec7274"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.aec7274","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]},"assertion":[{"value":"2025-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaec7274"}}