Velazquez-Rivera Eric, Dey Oyshi, Kim Nayoon S, Cao Wenhao, Ye Qiao, Gao Pan, Thai Andy, Nguyen Jason K, Zhang Hai, Ting Jonathan T, Gopi M, Ren Bing, Holmes Todd C, Xu Xiangmin
Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA.
Neuron. 2025 May 21;113(10):1562-1578.e6. doi: 10.1016/j.neuron.2025.03.031.
Brain endothelial cells (BECs) in brain vasculature are critical structural and functional components of the blood brain barrier (BBB). Adeno-associated virus (AAV) capsids have previously been genetically engineered to confer specificity to endothelial cells, but these capsids show limited endothelial cell specificity that varies by delivery conditions. We developed a set of new BEC-enhancer AAV vectors that specifically target BECs based on the cis-regulatory elements identified from single-cell epigenetic datasets. Ex vivo and in vivo characterization of BEC-enhancer AAVs in wild-type, Ai9 reporter, and Alzheimer's disease model mouse brains show their utility for high transduction selectivity of the BECs with little off-target transduction in the liver. Our BEC-enhancer AAVs target the brain vasculature by systemic administration and can be minimally invasive in terms of the route of administration. They are useful new tools for delivering genetic payloads specifically to BECs for normal and diseased brain studies.
脑血管中的脑内皮细胞（BECs）是血脑屏障（BBB）关键的结构和功能组成部分。腺相关病毒（AAV）衣壳此前已通过基因工程改造以赋予其对内皮细胞的特异性，但这些衣壳显示出有限的内皮细胞特异性，且会因递送条件而异。我们基于从单细胞表观遗传数据集中鉴定出的顺式调控元件，开发了一组新的BEC增强型AAV载体，可特异性靶向BECs。对野生型、Ai9报告基因小鼠和阿尔茨海默病模型小鼠脑内的BEC增强型AAV进行的体外和体内表征表明，它们可用于对BECs进行高转导选择性，且在肝脏中的脱靶转导极少。我们的BEC增强型AAV通过全身给药靶向脑血管，就给药途径而言，其侵入性可降至最低。它们是将基因载荷特异性递送至BECs以用于正常和患病脑研究的有用新工具。
