{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:56:26Z","timestamp":1790812586167,"version":"4.1.0"},"reference-count":53,"publisher":"SAGE Publications","issue":"21-22","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2026,11,1]]},"abstract":"<jats:p>\n                    Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers\n                    <jats:italic toggle=\"yes\">Parkin<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Bnip3,<\/jats:italic>\n                    mitochondria biogenesis marker\n                    <jats:italic toggle=\"yes\">Pgc1\u03b1 and<\/jats:italic>\n                    mitochondrial DNA-encoded subunits of complex IV,\n                    <jats:italic toggle=\"yes\">Cox1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Cox3<\/jats:italic>\n                    . In addition, the LC-II\/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.\n                  <\/jats:p>","DOI":"10.1177\/10430342261466685","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:38:19Z","timestamp":1783593499000},"page":"1045-1055","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein\u00a0Mouse Model of Hereditary Inclusion Body Myositis"],"prefix":"10.1177","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5739-5419","authenticated-orcid":false,"given":"Burcak","family":"Ozes","sequence":"first","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingying","family":"Tong","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Myers","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Moss","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7927-887X","authenticated-orcid":false,"given":"Edward","family":"Son","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9904-9140","authenticated-orcid":false,"given":"Tatyana A.","family":"Vetter","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Vasquez-Martinez","sequence":"additional","affiliation":[{"name":"Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Zepeda-Orozco","sequence":"additional","affiliation":[{"name":"Kidney and Urinary Tract Research Center, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"},{"name":"Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2974-3943","authenticated-orcid":false,"given":"Zarife","family":"Sahenk","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA"},{"name":"Department of Pediatrics and Neurology, Nationwide Children\u2019s Hospital, The Ohio State University, Columbus, Ohio, USA"},{"name":"Department of Pathology and Laboratory Medicine, Nationwide Children\u2019s Hospital, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.02.042"},{"key":"e_1_3_2_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105182"},{"issue":"18","key":"e_1_3_2_4_1","first-page":"3877","article-title":"The VCP\/p97 system at a glance: Connecting cellular function to disease pathogenesis","volume":"127","author":"Meyer H","year":"2014","unstructured":"3.Meyer H, , Weihl CC. The VCP\/p97 system at a glance: Connecting cellular function to disease pathogenesis. J Cell Sci 2014;127(Pt 18):3877\u20133883.","journal-title":"J Cell Sci"},{"key":"e_1_3_2_5_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200908115"},{"key":"e_1_3_2_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23041939"},{"key":"e_1_3_2_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.2.626-634.2002"},{"key":"e_1_3_2_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11020"},{"key":"e_1_3_2_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101936"},{"key":"e_1_3_2_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvi028"},{"key":"e_1_3_2_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21113842"},{"key":"e_1_3_2_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2016.00079"},{"key":"e_1_3_2_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.02.028"},{"key":"e_1_3_2_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1332"},{"key":"e_1_3_2_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27097"},{"key":"e_1_3_2_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2016.05.001"},{"key":"e_1_3_2_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2015.02.004"},{"key":"e_1_3_2_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2010.203"},{"key":"e_1_3_2_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2016.04.007"},{"key":"e_1_3_2_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1803130115"},{"key":"e_1_3_2_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016828"},{"key":"e_1_3_2_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq050"},{"key":"e_1_3_2_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/00125817-200007000-00006"},{"key":"e_1_3_2_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2009.01.009"},{"key":"e_1_3_2_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.23522"},{"key":"e_1_3_2_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omta.2026.201687"},{"key":"e_1_3_2_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12646"},{"key":"e_1_3_2_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.02.029"},{"key":"e_1_3_2_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01503-7"},{"key":"e_1_3_2_30_1","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x202010504"},{"key":"e_1_3_2_31_1","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/5346483"},{"key":"e_1_3_2_32_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.267419.115"},{"key":"e_1_3_2_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900992200"},{"key":"e_1_3_2_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/nen.0b013e31803020b9"},{"key":"e_1_3_2_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1504-6"},{"key":"e_1_3_2_36_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01091-14"},{"key":"e_1_3_2_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2021.113066"},{"key":"e_1_3_2_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-00726-x"},{"key":"e_1_3_2_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00234"},{"key":"e_1_3_2_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.08.023"},{"key":"e_1_3_2_41_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20220648"},{"key":"e_1_3_2_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43556-021-00043-2"},{"key":"e_1_3_2_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00016"},{"key":"e_1_3_2_44_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-02-0227"},{"key":"e_1_3_2_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.05.041"},{"key":"e_1_3_2_46_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011338"},{"key":"e_1_3_2_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.10.015"},{"key":"e_1_3_2_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.08.021"},{"key":"e_1_3_2_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410390615"},{"key":"e_1_3_2_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2019.02.001"},{"key":"e_1_3_2_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.054"},{"key":"e_1_3_2_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2016.07.019"},{"key":"e_1_3_2_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.08.012"},{"key":"e_1_3_2_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706304200"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10430342261466685","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10430342261466685","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10430342261466685","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:20:21Z","timestamp":1790810421000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10430342261466685"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":53,"journal-issue":{"issue":"21-22","published-print":{"date-parts":[[2026,11,1]]}},"alternative-id":["10.1177\/10430342261466685"],"URL":"https:\/\/doi.org\/10.1177\/10430342261466685","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]}}}