{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:15:49Z","timestamp":1786115749652,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,3]]},"group-title":"Molecular Biology","reference-count":14,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K01HL169413"],"award-info":[{"award-number":["K01HL169413"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R03HL183114"],"award-info":[{"award-number":["R03HL183114"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32AR083870"],"award-info":[{"award-number":["T32AR083870"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"crossref","award":["https:\/\/doi.org\/10.55762\/pc.gr.157032"],"award-info":[{"award-number":["https:\/\/doi.org\/10.55762\/pc.gr.157032"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["https:\/\/doi.org\/10.58275\/AHA.24CDA1259424.pc.gr.193591"],"award-info":[{"award-number":["https:\/\/doi.org\/10.58275\/AHA.24CDA1259424.pc.gr.193591"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Duchenne muscular dystrophy (DMD) is an X-linked muscle wasting disorder marked by lack of dystrophin expression. Symptoms include loss of ambulation, respiratory problems, and cardiac complications with heart failure being the leading cause of death. Dystrophin transduces force from the actin cytoskeleton to the extracellular matrix to protect cells during muscle contraction. Restoration of dystrophin expression by gene transfer holds promise in addressing the root cause of disease. We compared the changes to transcriptional profiles after gene transfer by adeno-associated virus or lentivirus to examine whether viral treatment alone impacts cell homeostasis. We delivered GFP to cardiomyocytes differentiated from induced pluripotent stem cells (iPSCs) with DMD mutations. Global transcriptional profiling revealed a downregulation of metabolic genes after lentiviral transduction compared to untreated controls. In both AAV and lentivirus-treated DMD iPSC-cardiomyocytes, we observed an activation of the p53 DNA damage response in addition to a downregulation of cell cycle genes, suggesting stress-induced G2\/M checkpoint arrest following viral delivery. These findings demonstrate that gene therapy mediated by viral vectors activates cell stress pathways. Interventions to mitigate these stress responses may be necessary for safe and effective gene transfer in diseased cells.<\/jats:p>","DOI":"10.64898\/2026.07.31.742163","type":"posted-content","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:25:27Z","timestamp":1785763527000},"source":"Crossref","is-referenced-by-count":0,"title":["AAV and lentiviral transduction in Duchenne muscular dystrophy cardiomyocytes activate cell stress responses"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8871-4296","authenticated-orcid":false,"given":"Elaine C.","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Muscle Biology and Disease Research Center, University of California, Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8736-8426","authenticated-orcid":false,"given":"Abiageal R.","family":"Keegan","sequence":"additional","affiliation":[{"name":"Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Muscle Biology and Disease Research Center, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Mathematical, Computational, and Systems Biology Graduate Program, University of California, Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3010-0275","authenticated-orcid":false,"given":"Asuka","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Muscle Biology and Disease Research Center, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA"},{"name":"Edwards Lifesciences Foundation Cardiovascular Innovation and Research Center, University of California, Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080521550870000_2026.07.31.742163v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.011"},{"issue":"1","key":"2026080521550870000_2026.07.31.742163v1.2","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/mas.21823","article-title":"Characterization of the dystrophin-associated protein complex by mass spectrometry","volume":"43","year":"2024","journal-title":"Mass Spectrom Rev"},{"key":"2026080521550870000_2026.07.31.742163v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-018-0177-7"},{"key":"2026080521550870000_2026.07.31.742163v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.02.081"},{"key":"2026080521550870000_2026.07.31.742163v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164680"},{"key":"2026080521550870000_2026.07.31.742163v1.6","unstructured":"Research C for BE and . FDA Investigating Deaths Due to Acute Liver Failure in Non-ambulatory Duchenne Muscular Dystrophy Patients Following ELEVIDYS. FDA [Internet]. 2025 Jun 25 [cited 2026 May 27]. Available from: https:\/\/www.fda.gov\/vaccines-blood-biologics\/safety-availability-biologics\/fda-investigating-deaths-due-acute-liver-failure-non-ambulatory-duchenne-muscular-dystrophy-patients"},{"key":"2026080521550870000_2026.07.31.742163v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.10.015"},{"issue":"4","key":"2026080521550870000_2026.07.31.742163v1.8","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.ymthe.2025.12.067","article-title":"Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies","volume":"34","year":"2026","journal-title":"Mol Ther J Am Soc Gene Ther"},{"issue":"2","key":"2026080521550870000_2026.07.31.742163v1.9","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1177\/22143602241303357","article-title":"Taking ACTION to detect myocarditis related to recombinant gene transfer therapy for Duchenne Muscular Dystrophy; Consensus recommendations for cardiac surveillance","volume":"12","year":"2025","journal-title":"J Neuromuscul Dis"},{"key":"2026080521550870000_2026.07.31.742163v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2023.06.002"},{"issue":"1","key":"2026080521550870000_2026.07.31.742163v1.11","doi-asserted-by":"crossref","first-page":"3694","DOI":"10.1038\/s41467-025-58778-3","article-title":"AAV vectors trigger DNA damage response-dependent pro-inflammatory signalling in human iPSC-derived CNS models and mouse brain","volume":"16","year":"2025","journal-title":"Nat Commun"},{"issue":"6","key":"2026080521550870000_2026.07.31.742163v1.12","doi-asserted-by":"crossref","first-page":"e2209967120","DOI":"10.1073\/pnas.2209967120","article-title":"TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs","volume":"120","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"2026080521550870000_2026.07.31.742163v1.13","doi-asserted-by":"crossref","first-page":"201801","DOI":"10.1016\/j.omta.2026.201801","article-title":"Microdystrophins partially rescue deficits of duchenne muscular dystrophy iPSC-cardiomyocytes","volume":"34","year":"2026","journal-title":"Mol Ther Adv"},{"issue":"9","key":"2026080521550870000_2026.07.31.742163v1.14","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1016\/j.stemcr.2021.04.018","article-title":"Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes","volume":"16","year":"2021","journal-title":"Stem Cell Rep"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.31.742163","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:55:15Z","timestamp":1785992115000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.31.742163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":14,"URL":"https:\/\/doi.org\/10.64898\/2026.07.31.742163","relation":{},"subject":[],"published":{"date-parts":[[2026,8,3]]},"subtype":"preprint"}}