A High-Efficiency AAV for Endothelial Cell Transduction Throughout the Central Nervous System.
A High-Efficiency AAV for Endothelial Cell Transduction Throughout the Central Nervous System.
复制标题
DOI：
10.1038/s44161-022-00046-4
复制
发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Deverman, Benjamin E
中科院分区：
文献类型：
--
作者：
Krolak, Trevor;Chan, Ken Y;Kaplan, Luke;Huang, Qin;Wu, Jason;Zheng, Qingxia;Kozareva, Velina;Beddow, Thomas;Tobey, Isabelle G;Pacouret, Simon;Chen, Albert T;Chan, Yujia A;Ryvkin, Daniel;Gu, Chenghua;Deverman, Benjamin E
内皮细胞在神经系统功能中发挥着至关重要的作用，越来越多的证据表明内皮细胞损伤是多种神经系统疾病的主要原因。然而，在体内对这些细胞进行基因检测的工具仍然有限。在这里，我们描述了 AAV-BI30，一种能够特异性、有效地在整个中枢神经系统中转导内皮细胞的衣壳。在相对较低的全身剂量下，该载体可转导成年 C57BL/6 小鼠大脑、视网膜和脊髓脉管系统中的大部分动脉、毛细血管和静脉内皮细胞。此外，我们还发现，AAV-BI30 能够在多种小鼠品系和大鼠的体内以及体外对人脑微血管内皮细胞中的内皮细胞进行强有力的转导。最后，我们证明了 AAV-BI30 在中枢神经系统中实现高效且内皮特异性 Cre 介导的基因操作的能力。这种特性的组合使得 AAV-BI30 非常适合解决神经血管生物学中的突出研究问题，并有助于开发治疗疾病中内皮功能障碍的疗法。
Endothelial cells have a crucial role in nervous system function, and mounting evidence points to endothelial impairment as a major contributor to a wide range of neurological diseases. However, tools to genetically interrogate these cells in vivo remain limited. Here, we describe AAV-BI30, a capsid that specifically and efficiently transduces endothelial cells throughout the central nervous system. At relatively low systemic doses, this vector transduces the majority of arterial, capillary, and venous endothelial cells in the brain, retina, and spinal cord vasculature of adult C57BL/6 mice. Furthermore, we show that AAV-BI30 robustly transduces endothelial cells in multiple mouse strains and rats in vivo and human brain microvascular endothelial cells in vitro. Finally, we demonstrate AAV-BI30’s capacity to achieve efficient and endothelial-specific Cre-mediated gene manipulation in the central nervous system. This combination of attributes makes AAV-BI30 uniquely well-suited to address outstanding research questions in neurovascular biology and aid the development of therapeutics to remediate endothelial dysfunction in disease.