Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates.
Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates.
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DOI：
10.1038/s41467-023-38582-7
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发表时间：
2023-06-08
影响因子：
16.6
通讯作者：
Gradinaru, Viviana
中科院分区：
文献类型：
--
作者：
Chen, Xinhong;Wolfe, Damien A.;Bindu, Dhanesh Sivadasan;Zhang, Mengying;Taskin, Naz;Goertsen, David;Shay, Timothy F.;Sullivan, Erin E.;Huang, Sheng-Fu;Kumar, Sripriya Ravindra;Arokiaraj, Cynthia M.;Plattner, Viktor M.;Campos, Lillian J.;Mich, John K.;Monet, Deja;Ngo, Victoria;Ding, Xiaozhe;Omstead, Victoria;Weed, Natalie;Bishaw, Yeme;Gore, Bryan B.;Lein, Ed S.;Akrami, Athena;Miller, Cory;Levi, Boaz P.;Keller, Annika;Ting, Jonathan T.;Fox, Andrew S.;Eroglu, Cagla;Gradinaru, Viviana
将基因有效地并特异性地跨物种递送到脑血管系统并穿过脑血管系统仍然是解决神经系统疾病的关键挑战。我们已经将腺相关病毒（AAV 9）衣壳进化成载体，在具有不同遗传背景的野生型小鼠和大鼠中全身给药后特异性和有效地抑制脑内皮细胞。这些AAV还在非人灵长类动物（绒猴和恒河猴）和离体人脑切片中表现出上级的CNS转导，尽管内皮嗜性在物种间不保守。衣壳修饰从AAV 9翻译为其他血清型，如AAV 1和AAV-DJ，使得能够在小鼠中进行顺序AAV施用的血清型转换。我们证明，内皮特异性小鼠衣壳可用于基因工程的血脑屏障，通过将小鼠脑血管系统转化为一个功能性的生物工厂。我们将这种方法应用于Hevin基因敲除小鼠，其中AAV-X1介导的突触发生蛋白Sparcl 1/Hevin在脑内皮细胞中的异位表达挽救了突触缺陷。将基因有效地和特异性地跨物种递送到脑血管系统并穿过脑血管系统仍然具有挑战性。在这里，作者表明，具有血清型灵活性的内皮特异性AAV能够在遗传多样性啮齿动物中重新给药并将脑血管系统转化为体内生物工厂。在灵长类动物中，这些载体穿过血脑屏障并显示出广泛的向性。
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 in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo 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. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits. Delivering genes to and across the brain vasculature efficiently and specifically across species remains challenging. Here, the authors show that endothelial-specific AAVs with serotype flexibility enable redosing and transform the brain vasculature into an in vivo biofactory in genetically diverse rodents. In primates, these vectors cross the blood-brain-barrier and show broad tropism.
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影响因子：
16.6
作者：
Adachi, Kei;Enoki, Tatsuji;Nakai, Hiroyuki
通讯作者：
Nakai, Hiroyuki
影响因子：
16.2
作者：
Chen, Xinhong;Kumar, Sripriya Ravindra;Adams, Cameron D.;Yang, Daping;Wang, Tongtong;Wolfe, Damien A.;Arokiaraj, Cynthia M.;Ngo, Victoria;Campos, Lillian J.;Griffiths, Jessica A.;Ichiki, Takako;Mazmanian, Sarkis K.;Osborne, Peregrine B.;Keast, Janet R.;Miller, Cory T.;Fox, Andrew S.;Chiu, Isaac M.;Gradinaru, Viviana
通讯作者：
Gradinaru, Viviana
DOI：
10.3791/2270
发表时间：
2010-11-16
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ippolito, Dominic M;Eroglu, Cagla
通讯作者：
Eroglu, Cagla
影响因子：
4.2
作者：
Bortolussi, Giulia;Zentillin, Lorena;Muro, Andres F.
通讯作者：
Muro, Andres F.
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V