Chen Xinhong, Wolfe Damien A, Bindu Dhanesh Sivadasan, Zhang Mengying, Taskin Naz, Goertsen David, Shay Timothy F, Sullivan Erin, Huang Sheng-Fu, Kumar Sripriya Ravindra, Arokiaraj Cynthia M, Plattner Viktor, Campos Lillian J, Mich John, Monet Deja, Ngo Victoria, Ding Xiaozhe, Omstead Victoria, Weed Natalie, Bishaw Yeme, Gore Bryan, Lein Ed S, Akrami Athena, Miller Cory, Levi Boaz P, Keller Annika, Ting Jonathan T, Fox Andrew S, Eroglu Cagla, Gradinaru Viviana
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
bioRxiv. 2023 Jan 13:2023.01.12.523844. doi: 10.1101/2023.01.12.523844.
Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds and rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and human brain slices although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. Vasculature-secreted Hevin (a synaptogenic protein) rescued synaptic deficits in a mouse model.
在跨物种的情况下，高效且特异性地将基因递送至脑脉管系统并穿越该系统，仍然是治疗神经疾病的一项关键挑战。我们已将腺相关病毒（AAV9）衣壳改造为载体，在具有不同遗传背景的野生型小鼠和大鼠中进行全身给药后，这些载体能够特异性且高效地转导脑内皮细胞。这些AAV在非人灵长类动物（狨猴和恒河猴）以及人脑切片中也表现出对中枢神经系统的卓越转导能力，尽管内皮嗜性在不同物种间并不保守。衣壳修饰可从AAV9转化至其他血清型，如AAV1和AAV-DJ，从而能够在小鼠中进行血清型转换以便序贯给予AAV。我们证明，内皮特异性的小鼠衣壳可通过将小鼠脑血管系统转变为功能性生物工厂，用于对血脑屏障进行基因工程改造。血管分泌的Hevin（一种促突触生成蛋白）挽救了小鼠模型中的突触缺陷。
