小柯机器人

上海交通大学医学院松江研究院仇子龙等研究人员合作发现，全脑体内碱基编辑可逆转Mef2c突变小鼠的行为变化。这一研究成果于2023年11月27日在线发表在国际学术期刊《自然—神经科学》上。

研究人员开发了一种载脂蛋白B信使RNA编辑酶、催化多肽嵌入式胞嘧啶碱基编辑器（AeCBE）系统，用于将C-G转换为T-A碱基对。研究人员通过在小鼠体内将AeCBE靶向与自闭症谱系障碍（ASD）相关的MEF2C基因突变（c.104T>C，p.L35P），证明了它的有效性。研究人员首先构建了Mef2c^L35P杂合子小鼠。雄性杂合小鼠表现出多动、重复行为和社交异常。

然后，研究人员通过静脉注射跨越血脑屏障的腺相关病毒，对AeCBE进行编程，以编辑小鼠大脑中Mef2c突变的C-G碱基对。这种处理方法成功恢复了多个脑区的Mef2c蛋白水平，并逆转了Mef2c突变小鼠的行为异常。这项研究提出了一种体内碱基编辑范例，有可能纠正大脑中的单碱基基因突变。

据介绍，通过全脑基因组编辑来纠正单碱基突变、减少或逆转ASD动物模型中的行为变化，目前尚未实现。

附：英文原文

Title: Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice

Author: Li, Wei-Ke, Zhang, Shu-Qian, Peng, Wan-Ling, Shi, Yu-Han, Yuan, Bo, Yuan, Yi-Ting, Xue, Zhen-Yu, Wang, Jin-Cheng, Han, Wen-Jian, Chen, Zhi-Fang, Shan, Shi-Fang, Xue, Bi-Qing, Chen, Jin-Long, Zhang, Cheng, Zhu, Shu-Jia, Tai, Yi-Lin, Cheng, Tian-Lin, Qiu, Zi-Long

Issue&Volume: 2023-11-27

Abstract: Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood–brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

DOI: 10.1038/s41593-023-01499-x

Source: https://www.nature.com/articles/s41593-023-01499-x

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