Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (2): 704-714.doi: 10.4103/NRR.NRR-D-23-01802

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

Rubing Shi1 , Jing Ye1 , Ze Liu1 , Cheng Wang1 , Shengju Wu1 , Hui Shen1 , Qian Suo1 , Wanlu Li1 , Xiaosong He2 , Zhijun Zhang1 , Yaohui Tang1 , Guo-Yuan Yang1, *, Yongting Wang1, *   

  1. 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
  • Online:2026-02-15 Published:2025-05-24
  • Contact: Yongting Wang, PhD, yongting.wang@gmail.com; Guo-Yuan Yang, MD, PhD, gyyang@sjtu.edu.cn.
  • Supported by:
    This study was 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).

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Abstract: 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 (prestroke) 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.

Key words: AAV-PHP.eB, angiogenesis, basic fibroblast growth factor, gene therapy, ischemic stroke, Ly6A, neurogenesis, neurological function, transient middle cerebral artery occlusion, tropism