{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:15:06Z","timestamp":1788448506721,"version":"build-2803163510"},"reference-count":90,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014857","name":"National Natural Science Foundation of China-Guangdong Joint Fund","doi-asserted-by":"publisher","award":["2023A1515011719"],"award-info":[{"award-number":["2023A1515011719"]}],"id":[{"id":"10.13039\/501100014857","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>In vivo transcription factor (TF) \u2010mediated gene therapy through astrocyte\u2010to\u2010neuron (AtN) conversion has shown therapeutic effects on rodent and non\u2010human primate cortical ischemic injury in the subacute phase. However, in the clinic, subcortical regions including striatum as well as white matter are vulnerable regions of stroke, with millions of patients beyond subacute phase. In this study, we investigate whether TF\u2010mediated AtN conversion therapy can be extended to treat chronic\u2010phase ischemic stroke involving subcortical regions (e.g., striatum) and white matter, beyond cortical injuries.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rat middle cerebral artery occlusion (MCAO)\u2010like models were established to induce broad ischemic injuries including cortical and striatal regions. Then multiple rounds of TF\u2010mediated gene therapy treatments through adeno\u2010associated virus (AAV) system to cover the large\u2010scaled infarct areas were conducted in the chronic phase of the stroke models. Magnetic resonance imaging (MRI), [<jats:sup>18<\/jats:sup>F] FDG\u2010PET\/CT, behavioral tests, immunohistochemistry and bulk\u2010RNA seq were applied to evaluate the AtN conversion, tissue repair and functional recovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results revealed that administrated in the chronic phase of ischemic stroke, TF\u2010mediated gene therapy can efficiently regenerate new neurons in both cortical and striatal regions, and promote tissue repair in both grey and white matter. Compared with single round of AAV administration, multiple rounds of treatment regenerated more neurons and led to a significant functional recovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study demonstrates that TF\u2010mediated gene therapy has a broad therapeutic time window and can be applied multiple rounds to treat severe ischemic stroke, making it an attractive therapeutic intervention in the chronic phase after stroke, when current approaches are largely ineffective.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70448","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T06:02:08Z","timestamp":1747893728000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transcription Factor\u2010Based Gene Therapy Enables Functional Repair of Rat Following Chronic Ischemic Stroke"],"prefix":"10.1111","volume":"31","author":[{"given":"Tao","family":"Wang","sequence":"first","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanggong","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglei","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiying","family":"Wan","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Liao","sequence":"additional","affiliation":[{"name":"Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non\u2010Human Primate Research, GHM Institute of CNS Regeneration Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiming","family":"Zou","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non\u2010Human Primate Research, GHM Institute of CNS Regeneration Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non\u2010Human Primate Research, GHM Institute of CNS Regeneration Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Lei","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"},{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"},{"name":"Department of Nuclear Medicine and PET\/CT\u2010MRI Center The First Affiliated Hospital of Jinan University &amp; Institute of Molecular and Functional Imaging, Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"},{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"},{"name":"Department of Nuclear Medicine and PET\/CT\u2010MRI Center The First Affiliated Hospital of Jinan University &amp; Institute of Molecular and Functional Imaging, Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4632-5754","authenticated-orcid":false,"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong\u2010Hong Kong\u2010Macau Institute of CNS Regeneration (GHMICR) Jinan University  Guangzhou China"},{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"},{"name":"Department of Nuclear Medicine and PET\/CT\u2010MRI Center The First Affiliated Hospital of Jinan University &amp; Institute of Molecular and Functional Imaging, Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/17474930231181677"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241914848"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.1455"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319948"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2016.01.015"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.04.004"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24820"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910106107"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3267"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040843"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201745294"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.11.023"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2843"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.12.001"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.08.004"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.08.009"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2388-4"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.590008"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.09.003"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2021.102198"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14855-3"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4338"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.591883"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.612856"},{"issue":"3","key":"e_1_2_10_26_1","article-title":"Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery Following a Sensory\u2010Motor Cortical Stroke","volume":"12","author":"Livingston J. M.","year":"2024","journal-title":"Biomedicine"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.720078"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15833"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.1263"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1993.34"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.359"},{"key":"e_1_2_10_32_1","article-title":"Assessment of Sensorimotor Function in Mouse Models of Parkinson's Disease","volume":"76","author":"Fleming S. M.","year":"2013","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2017.07.039"},{"key":"e_1_2_10_34_1","article-title":"Endothelin\u20101 Induced Middle Cerebral Artery Occlusion Model for Ischemic Stroke With Laser Doppler Flowmetry Guidance in Rat","volume":"72","author":"Ansari S.","year":"2013","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.27.9.1616"},{"key":"e_1_2_10_36_1","article-title":"Focal Cerebral Ischemia Model by Endovascular Suture Occlusion of the Middle Cerebral Artery in the Rat","volume":"48","author":"Uluc K.","year":"2011","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.186"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36598-4"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.263194"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2016.04.005"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2018.07.039"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A1051"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3340\/jkns.2019.0046"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.762843"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184500"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2021.107848"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113518"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.117.018290"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197380"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-022-00984-y"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-22802-z"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02949-w"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-022-01078-5"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0043-1770352"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22850"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0201-09.2009"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.700297"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41536-022-00248-1"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35498-6"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24361"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47482-0"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0012-9"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.11.004"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106035"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2009.08.002"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.8140"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00294"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-016-0483-x"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-019-1516-2"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.07.007"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.08.012"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adi7828"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6221-11.2012"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109048"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27248-x"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3371"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2020.594170"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aav0492"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.755955"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.00703"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40070"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1159\/000490349"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2021.113685"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00201"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.04.022"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05689-0"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2015.04.039"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.147.6.1123"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22880"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.01.029"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.005"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70448","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T09:19:57Z","timestamp":1752743997000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":90,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1111\/cns.70448"],"URL":"https:\/\/doi.org\/10.1111\/cns.70448","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5]]},"assertion":[{"value":"2025-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70448"}}