{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:03:32Z","timestamp":1791443012130,"version":"4.3.3"},"reference-count":45,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":52,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"crossref","award":["1060372"],"award-info":[{"award-number":["1060372"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Association Fran\u00e7aise contre les Myopathies","award":["24777"],"award-info":[{"award-number":["24777"]}]},{"name":"Diabetes Research Center","award":["P30 DK017047"],"award-info":[{"award-number":["P30 DK017047"]}]},{"name":"Wellstone Center at the University of Washington","award":["P50 AR065139"],"award-info":[{"award-number":["P50 AR065139"]}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"crossref","award":["MD220097"],"award-info":[{"award-number":["MD220097"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Washington Center for Translational Muscle Research","award":["P30AR074990"],"award-info":[{"award-number":["P30AR074990"]}]},{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health","award":["R01HL128368"],"award-info":[{"award-number":["R01HL128368"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:p>\n                    Gene replacement therapies mediated by adeno-associated viral (AAV) vectors represent a promising approach for treating genetic diseases. However, their modest packaging capacity (~4.7 kb) remains an important constraint and significantly limits their application for genetic disorders involving large genes. A prominent example is Duchenne muscular dystrophy (DMD), whose protein product dystrophin is generated from a 11.2 kb segment of the\n                    <jats:italic>DMD<\/jats:italic>\n                    mRNA. Here, we explored methods that enable efficient expression of full-length dystrophin via triple AAV codelivery. This method exploits the protein\n                    <jats:italic>trans<\/jats:italic>\n                    -splicing mechanism mediated by split inteins. We identified a combination of efficient and specific split intein pairs that enabled the reconstitution of full-length dystrophin from 3 dystrophin fragments. We show that systemic delivery of low doses of the myotropic AAVMYO1 in\n                    <jats:italic>mdx<\/jats:italic>\n                    <jats:sup>4cv<\/jats:sup>\n                    mice led to efficient expression of full-length dystrophin in the hind limb, diaphragm, and heart muscles. Notably, muscle morphology and physiology were significantly improved in triple-AAV\u2013treated\n                    <jats:italic>mdx<\/jats:italic>\n                    <jats:sup>4cv<\/jats:sup>\n                    mice versus saline-treated controls. This method shows the feasibility of expressing large proteins from several fragments that were delivered using low doses of myotropic AAV vectors. It can be adapted to other large genes involved in disorders for which gene replacement remains challenged by the modest AAV cargo capacity.\n                  <\/jats:p>","DOI":"10.1172\/jci189075","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T12:00:32Z","timestamp":1749556832000},"source":"Crossref","is-referenced-by-count":14,"title":["Expression of full-length dystrophin reverses muscular dystrophy defects in young and old mdx4cv mice"],"prefix":"10.1172","volume":"135","author":[{"given":"Hichem","family":"Tasfaout","sequence":"first","affiliation":[{"name":"Department of Neurology and"},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy S.","family":"McMillen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, College of Engineering and School of Medicine, University of Washington, Seattle, Washington, USA."},{"name":"Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, USA."},{"name":"Mitochondria and Metabolism Center and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore R.","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Neurology and"},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"Halbert","sequence":"additional","affiliation":[{"name":"Department of Neurology and"},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3676-3830","authenticated-orcid":true,"given":"Rong","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, USA."},{"name":"Mitochondria and Metabolism Center and"},{"name":"Center for Translational Muscle Research, University of Washington, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Regnier","sequence":"additional","affiliation":[{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, Washington, USA."},{"name":"Department of Bioengineering, College of Engineering and School of Medicine, University of Washington, Seattle, Washington, USA."},{"name":"Center for Translational Muscle Research, University of Washington, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-0059","authenticated-orcid":true,"given":"Jeffrey S.","family":"Chamberlain","sequence":"additional","affiliation":[{"name":"Department of Neurology and"},{"name":"Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine, Seattle, Washington, USA."},{"name":"Center for Translational Muscle Research, University of Washington, Seattle, Washington, USA."},{"name":"Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13081370"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12050785"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.09.015"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0205-4"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/316842a0"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/322073a0"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nm0302-253"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nm1439"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000958"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.01.002"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2022.180"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36612"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.165869"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-021-00011-z"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2023.05.017"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.07.014"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad5143"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14454"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau1549"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1011367"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2013.164"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2013.210"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07710-8"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1039\/C3SC52951G"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.810180"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202115199"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2021.10.004"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav4523"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.10.015"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.02.002"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1092420109"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.018424"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00176-2023"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2016.07.020"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.162982"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2015.tb00638.x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-024-00494-6"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19230-w"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(91)90340-9"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.adp8179"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50569-6"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn4704"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.028"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.11.004"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7374-3_18"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/189075\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:15:59Z","timestamp":1779210959000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/189075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,10]]},"references-count":45,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,6,12]]},"published-print":{"date-parts":[[2025,8,1]]}},"alternative-id":["10.1172\/JCI189075"],"URL":"https:\/\/doi.org\/10.1172\/jci189075","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,10]]},"article-number":"e189075"}}