Songjiang Research Institute, Songjiang Hospital & MOE-Shanghai Key Laboratory for Children's Environmental Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
Nat Neurosci. 2024 Jan;27(1):116-128. doi: 10.1038/s41593-023-01499-x. Epub 2023 Nov 27.
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.
全脑基因组编辑以纠正自闭症谱系障碍（ASD）动物模型中的单碱基突变并减少或逆转行为变化尚未实现。我们开发了载脂蛋白 B 信使 RNA 编辑酶，催化多肽嵌入胞嘧啶碱基编辑器（AeCBE）系统，用于将 C·G 转换为 T·A 碱基对。我们通过将 AeCBE 靶向 MEF2C 基因（c.104T>C，p.L35P）的 ASD 相关突变在体内证明了其有效性在小鼠中。我们首先构建了 Mef2cL35P 杂合子小鼠。雄性杂合子小鼠表现出过度活跃、重复行为和社交异常。然后，我们通过静脉注射血脑屏障穿透的腺相关病毒，将 AeCBE 编程为编辑小鼠大脑中突变的 C·G 碱基对。这种治疗成功地恢复了几个脑区的 Mef2c 蛋白水平，并逆转了 Mef2c 突变小鼠的行为异常。我们的工作提出了一种体内碱基编辑范例，该范例可能有潜力纠正大脑中的单碱基基因突变。
