CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease
CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease
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DOI：
10.1172/jci92087
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发表时间：
2017-06-30
影响因子：
15.9
通讯作者：
Li, Xiao-Jiang
中科院分区：
文献类型：
--
作者：
Yang, Su;Chang, Renbao;Li, Xiao-Jiang
亨廷顿病是由亨廷顿基因（HTT）中的多聚谷氨酰胺重复序列引起的神经退行性疾病。尽管已经探索了抑制突变HTT（mHTT）的表达作为治疗亨廷顿氏病的治疗策略，但是考虑到小鼠中Htt的丧失可能导致胚胎致死，已经进行了相当大的努力来开发mHTT表达的等位基因特异性抑制。目前尚不清楚在成年人大脑中HTT的消耗，无论其等位基因如何，是否可能是一种安全的治疗方法。在这里，我们报告了使用CRISPR/Cas9介导的失活永久抑制mHTT表达小鼠（HD 140 Q-敲入小鼠）纹状体中的内源性mHTT表达，有效地消除了HTT聚集体并减弱了早期神经病理学。成年HD 140 Q基因敲入小鼠纹状体神经元细胞中mHTT表达的减少不影响生存能力，但减轻了运动缺陷。我们的研究表明，非等位基因特异性CRISPR/Cas9介导的基因编辑可用于有效和永久地消除成人大脑中多聚谷氨酰胺扩增介导的神经元毒性。
Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT-expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain.