中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (2): 704-714.doi: 10.4103/NRR.NRR-D-23-01802

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

腺相关病毒载体AAV-PHP.eB在缺血性脑卒中的靶向性特征:有助于神经与血管再生

  

  • 出版日期:2026-02-15 发布日期:2025-05-24

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).

摘要:

AAV-PHP.eB是一种人工筛选开发的腺相关病毒,与其他全身给药的腺相关病毒相比,其可更有效地穿越血脑屏障,并靶向神经元。尽管它已被应用于多种疾病模型,但其在脑血管疾病下的靶向性特征仍不明朗。此次实验探索了AAV-PHP.eB在缺血性脑卒中中的靶向性特征,并研究了其介导碱性成纤维细胞生长因子(bFGF)基因治疗缺血性脑卒中的疗效。研究在脑卒中前14d或脑卒中后1d时静脉注射AAV-PHP.eB-bFGF。结果显示,缺血性脑卒中发生后,AAV-PHP.eB的靶向性由神经元转变为部分内皮细胞与星形胶质细胞,且AAV-PHP.eB的内皮细胞靶向性与内皮细胞膜受体Ly6A的表达有关。同时AAV-PHP.eB介导的bFGF过表达可有效改善了缺血性脑卒中后的神经行为结果,并促进了神经发生和血管生成。这一结果提示,在神经系统疾病中应用AAV-PHP.eB进行基因治疗时应考虑潜在的靶向性转变,并提出了bFGF基因疗法可作为治疗缺血性脑卒中的潜在策略。

https://orcid.org/0000-0003-3105-9307 (Guo-Yuan Yang); https://orcid.org/0000-0002-5841-6557 (Yongting Wang)

关键词: AAV-PHP.eB, 碱性成纤维细胞生长因子, 基因治疗, 缺血性脑卒中, 靶向性, 神经发生, 血管生成, 神经功能, Ly6A, 短暂性大脑中动脉闭塞

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