{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:57:17Z","timestamp":1793055437830,"version":"4.5.0"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"837","funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["153056"],"award-info":[{"award-number":["153056"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,2,18]]},"abstract":"<jats:p>\n                    Adeno-associated virus (AAV)\u2013mediated liver injury is the primary off-target toxicity observed with viral gene therapy. Understanding of the underlying mechanisms has been hindered by the fact that murine studies poorly model AAV toxicity. The X-linked myotubular myopathy (XLMTM) gene therapy program epitomizes this therapeutic discordance, because a subset of participants treated with AAV8-driven myotubularin (\n                    <jats:italic toggle=\"yes\">MTM1<\/jats:italic>\n                    ) gene replacement developed fatal liver injury that was not predicted by preclinical models. Here, we investigated a multihit hypothesis whereby loss of\n                    <jats:italic toggle=\"yes\">Mtm1<\/jats:italic>\n                    interacts with the postweaning environment to precipitate liver injury in XLMTM mouse models.\n                    <jats:italic toggle=\"yes\">Mtm1<\/jats:italic>\n                    knockout (KO) mice fed purified ingredient diets manifested liver dysfunction that mirrored patient clinical presentations, including elevated plasma transaminases, altered bile acid composition, and histological features of cholestasis. We further demonstrated a role for MTM1 in maintaining hepatocyte structure and localization of the bile salt export pump. Liver-specific deletion of\n                    <jats:italic toggle=\"yes\">Mtm1<\/jats:italic>\n                    recapitulated many of these features, supporting a liver-autonomous role for\n                    <jats:italic toggle=\"yes\">Mtm1<\/jats:italic>\n                    . Treatment of diet-sensitized mice with AAV8-driven gene therapy increased the susceptibility of cholestasis in global KO mice and induced liver injury in wild-type mice. Last, as a proof of concept, we treated global KO mice with lipid nanoparticle\n                    <jats:italic toggle=\"yes\">MTM1<\/jats:italic>\n                    gene replacement, which prevented development of key histopathological liver abnormalities. These findings provide critical insights into the environmental precipitants and molecular mechanisms of liver dysfunction in XLMTM and the adverse events seen in viral gene therapy studies and more broadly offer a framework to model AAV-associated toxicity and identify potential therapeutic interventions.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adr1483","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T18:58:48Z","timestamp":1771441128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["AAV8 gene therapy and dietary insults together precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5131-9543","authenticated-orcid":true,"given":"Emanuela","family":"Pannia","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Simonian","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrin","family":"Sabha","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nika","family":"Maani","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1764-1149","authenticated-orcid":true,"given":"Sophie","family":"Karolczak","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Raileanu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4199-7551","authenticated-orcid":true,"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[{"name":"Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott &amp; White Research Institute, Dallas, TX 75204, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-0009","authenticated-orcid":true,"given":"Gaia","family":"Andreoletti","sequence":"additional","affiliation":[{"name":"Astellas Gene Therapies, San Francisco, CA 94108, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-6078","authenticated-orcid":true,"given":"Rachel D.","family":"Edgar","sequence":"additional","affiliation":[{"name":"Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, Ontario, M5G 2N2, Canada."},{"name":"Donnelly Centre, University of Toronto, Toronto, Ontario, M5S 3E1, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8036-1425","authenticated-orcid":true,"given":"Sonya A.","family":"MacParland","sequence":"additional","affiliation":[{"name":"Ajmera Transplant Centre, Toronto General Research Institute, University Health Network, Toronto, Ontario, M5G 2N2, Canada."},{"name":"Department of Immunology, University of Toronto, Toronto, Ontario, M5S 3K3, Canada."},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 3K3, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3621-0549","authenticated-orcid":true,"given":"Aleksandra","family":"Mitina","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9733-2516","authenticated-orcid":true,"given":"Clara E.","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Human Health Sciences, College of Biological Science, University of Guelph, Guelph, Ontario, N1G 2W1, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0731-3950","authenticated-orcid":true,"given":"Michael W.","family":"Lawlor","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI 53226-3522, USA."},{"name":"Diverge Translational Science Laboratory Milwaukee, WI 53204, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6289-4711","authenticated-orcid":true,"given":"Kirsten E.","family":"Coleman","sequence":"additional","affiliation":[{"name":"Powell Gene Therapy Center, Department of Pediatrics, University of Florida, Gainesville, FL 32601, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7302-1756","authenticated-orcid":true,"given":"Barry J.","family":"Byrne","sequence":"additional","affiliation":[{"name":"Powell Gene Therapy Center, Department of Pediatrics, University of Florida, Gainesville, FL 32601, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9239-3846","authenticated-orcid":true,"given":"Ashish R.","family":"Deshwar","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."},{"name":"Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Developmental and Stem Cell Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."},{"name":"Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, M5G 1E8, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-4169","authenticated-orcid":true,"given":"James J.","family":"Dowling","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, M5G 0A4, Canada."},{"name":"Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada."},{"name":"Division of Neurology, Hospital for Sick Children, Toronto, Ontario, M5G 1E8, Canada."},{"name":"Departments of Neurology and Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2021.08.003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-3-26"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10033"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(02)00153-0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004415"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104894"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00313-7"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3233\/JND-210712"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-021-02055-1"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3233\/JND-210781"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007523"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.02.004"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI166275"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.726468"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.04.045"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v12.i8.423"},{"key":"e_1_3_2_18_2","first-page":"23","article-title":"Correlation between cholestasis and infection","volume":"13","author":"Tanasescu C.","year":"2004","unstructured":"C. Tanasescu, Correlation between cholestasis and infection. Rom. J. Gastroenterol. 13, 23\u201327 (2004).","journal-title":"Rom. J. Gastroenterol."},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2019.105422"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2023.2181930"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/cdn\/nzaa031"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12986-018-0243-5"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049342"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/127.5.838S"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.14309\/crj.0000000000001240"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.7150\/jca.44697"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2006-0036"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu12010047"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201900580"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00544"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2022.2083417"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0205055"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-46331-5"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114519000680"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166320"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2015.00084"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28356"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.119"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66025"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-96966-5"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.329318"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.10.041"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020281"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1003"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2015.05.010"},{"key":"e_1_3_2_46_2","first-page":"31","article-title":"Consider the chemokines: A review of the interplay between chemokines and T cell subset function","volume":"24","author":"Strazza M.","year":"2017","unstructured":"M. Strazza, A. Mor, Consider the chemokines: A review of the interplay between chemokines and T cell subset function. Discov. Med. 24, 31\u201339 (2017).","journal-title":"Discov. Med."},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1302"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00071.2004"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808667200"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.3390\/cimb44100341"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2013.05.001"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpg.2010.07.010"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/3034"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000003399"},{"key":"e_1_3_2_55_2","first-page":"219","article-title":"A link between intrahepatic cholestasis and genetic variations in intracellular trafficking regulators","volume":"10","author":"Li Q.","year":"2021","unstructured":"Q. Li, Y. Sun, S. C. D. van IJzendoorn, A link between intrahepatic cholestasis and genetic variations in intracellular trafficking regulators. Biology 10, 219 (2021).","journal-title":"Biology"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1177\/01926233231201408"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.05.003"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2019.255"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111638"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/nutrit\/nuz109"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.212498399"},{"key":"e_1_3_2_62_2","unstructured":"asmitina asmitina\/cld-lipids: Lipidome profile in CLD (v1.1). Zenodo (2024); https:\/\/doi.org\/10.5281\/zenodo.10611962."},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpmo.40"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/ismej.2012.8"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.3390\/nu13124510"},{"key":"e_1_3_2_66_2","first-page":"27663","article-title":"Analysis of composition of microbiomes: A novel method for studying microbial composition","volume":"26","author":"Mandal S.","year":"2015","unstructured":"S. Mandal, W. Van Treuren, R. A. White, M. Eggesbo, R. Knight, S. D. Peddada, Analysis of composition of microbiomes: A novel method for studying microbial composition. Microb. Ecol. Health Dis. 26, 27663 (2015).","journal-title":"Microb. Ecol. Health Dis."},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw354"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1652-y"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1102-2"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103233"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08023-x"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adr1483","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T16:00:51Z","timestamp":1776700851000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adr1483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":72,"journal-issue":{"issue":"837","published-print":{"date-parts":[[2026,2,18]]}},"alternative-id":["10.1126\/scitranslmed.adr1483"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adr1483","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]},"assertion":[{"value":"2024-06-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-31","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadr1483"}}