Tropism-shifted AAV-PHP.eB-mediated bFGF gene therapy promotes varied neurorestoration after ischemic stroke in mice  

作　　者：Rubing Shi Jing Ye Ze Liu Cheng Wang Shengju Wu Hui Shen Qian Suo Wanlu Li Xiaosong He Zhijun Zhang Yaohui Tang Guo-Yuan Yang Yongting Wang 

机构地区：[1]Med-X Research Institute and School of Biomedical Engineering,Shanghai Jiao Tong University,Shanghai,China [2]Department of Emergency,the Second Affiliated Hospital,Department of Human Anatomy,School of Basic Science,Guangzhou Medical University,Guangzhou,Guangdong Province,China

出　　处：《Neural Regeneration Research》2026年第2期704-714,共11页中国神经再生研究(英文版)

基　　金：supported by the National Natural Science Foundation of China,Nos.81870921(to YW),81974179(to ZZ),82271320(to ZZ),82071284(to YT);National Key R&D Program of China,No.2022YFA1603600(to ZZ),2019YFA0112000(to YT);Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY);Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY).

摘　　要：AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.

关 键 词：AAV-PHP.eB angiogenesis basic fibroblast growth factor gene therapy ischemic stroke Ly6A neurogenesis neurological function transient middle cerebral artery occlusion TROPISM 

分 类 号：R743.3[医药卫生—神经病学与精神病学]