[Cell] Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice

Summary

Conversion ofglial cells into functional neurons represents a potential therapeutic approachfor replenishing neuronal loss associated with neurodegenerative diseases andbrain injury. Previous attempts in this area using expression of transcriptionfactors were hindered by the low conversion efficiency and failure ofgenerating desired neuronal typesin vivo.Here, we report that downregulation of a single RNA-binding protein,polypyrimidine tract-binding protein 1 (Ptbp1),usingin vivoviraldelivery of a recently developed RNA-targeting CRISPR system CasRx, resulted inthe conversion of Müller glia into retinal ganglion cells (RGCs) with a highefficiency, leading to the alleviation of disease symptoms associated with RGCloss. Furthermore, this approach also induced neurons with dopaminergicfeatures in the striatum and alleviated motor defects in a Parkinson’s diseasemouse model. Thus, glia-to-neuron conversion by CasRx-mediatedPtbp1knockdown represents apromisingin vivogeneticapproach for treating a variety of disorders due to neuronal loss.

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神经胶质细胞向功能神经元的转化是修复神经退行性疾病和脑损伤相关神经元损失的一种潜在的治疗方法。先前在这一领域利用转录因子表达的尝试由于转换效率低和在体内无法产生所需的神经元类型而受阻。该研究中，研究人员首先在体外细胞系中筛选了高效抑制Ptbp1表达的gRNA，设计了特异性标记穆勒胶质细胞和在穆勒胶质细胞中表达CasRx的系统。所有元件以双质粒系统的形式被包装在AAV中并且通过视网膜下注射，特异性地在成年小鼠的穆勒胶质细胞中下调Ptbp1基因的表达。此外，该方法还诱导了纹状体中具有多巴胺能特征的神经元，并减轻了帕金森病小鼠模型的运动缺陷。因此，通过CasRx介导的Ptbp1基因敲除，胶质细胞向神经元的转化是一种很有前途的体内遗传学方法，可用于治疗由于神经元丢失而引起的各种疾病。

via : 原文

corresponding author : 杨辉 杨辉研究组

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最初我在一席上看了杨辉老师关于利用基因编辑治疗罕见病的报告，关于基因编辑的方法和原理杨老师做的科普非常通俗易懂，而且三个关键介绍的非常到位。对于利用基因编辑治疗疾病的设想，杨老师的专业性和前瞻性绝对是毋庸置疑的。

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90%的罕见病无药可治，我们能否用基因编辑做些什么？

重磅｜顶级杂志Cell发表辉大科学家团队关于神经退行性疾病治疗重大成果