小柯机器人

美国加州理工学院Viviana Gradinaru团队开发出在小鼠和狨猴中实现全脑转基因表达并降低肝脏靶向性的AAV衣壳变体。这一研究成果于2021年12月9日在线发表在国际学术期刊《自然—神经科学》上。

研究人员展示了腺相关病毒（AAV）在静脉注射后的器官特异性靶向，研究人员通过采用基于Cre-转基因的筛选平台和VP3的表面暴露AA452和AA460之间的AAV-PHP.eB顺序工程来实现。通过这种选择，研究人员确定了在C57BL/6J小鼠中富集于大脑并远离肝脏的衣壳变体。这种趋向性延伸到狨猴（Callithrix jacchus），使其在静脉注射后能以非侵入性的方式向狨猴的大脑传递基因。

值得注意的是，所发现的衣壳在大脑中产生了不同的转基因表达谱，其中一个对神经元表现出高度的特异性。在啮齿类动物和非人灵长类动物中，能够以神经元的特异性穿过血脑屏障的能力为基础研究和治疗提供了新的途径，而这是自然发生的血清型所无法达到的。

据介绍，基因干预正被越来越多地探索为治疗中枢神经系统衰弱性疾病的一种选择。基因疗法的安全性和有效性取决于在受影响的细胞中表达转基因，同时尽量减少非目标表达。

附：英文原文

Title: AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

Author: Goertsen, David, Flytzanis, Nicholas C., Goeden, Nick, Chuapoco, Miguel R., Cummins, Alexander, Chen, Yijing, Fan, Yingying, Zhang, Qiangge, Sharma, Jitendra, Duan, Yangyang, Wang, Liping, Feng, Guoping, Chen, Yu, Ip, Nancy Y., Pickel, James, Gradinaru, Viviana

Issue&Volume: 2021-12-09

Abstract: Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies rely upon expressing a transgene in affected cells while minimizing off-target expression. Here we show organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery, which we achieved by employing a Cre-transgenic-based screening platform and sequential engineering of AAV-PHP.eB between the surface-exposed AA452 and AA460 of VP3. From this selection, we identified capsid variants that were enriched in the brain and targeted away from the liver in C57BL/6J mice. This tropism extends to marmoset (Callithrix jacchus), enabling robust, non-invasive gene delivery to the marmoset brain after intravenous administration. Notably, the capsids identified result in distinct transgene expression profiles within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood–brain barrier with neuronal specificity in rodents and non-human primates enables new avenues for basic research and therapeutic possibilities unattainable with naturally occurring serotypes.

DOI: 10.1038/s41593-021-00969-4

Source: https://www.nature.com/articles/s41593-021-00969-4

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex