CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease

• Type of Material: Article
• Authors: Su Yang, Emory University; Renbao Chang, Emory University; Huiming Yang, Emory University; Ting Zhao, Emory University; Yan Hong, Emory University; Ha Eun Kong, Emory University; Xiaobo Sun, Emory University; Zhaohui Qin, Emory University; Peng Jin, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2017-06-30
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2017, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI92087
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 127
• Issue: 7
• Start Page: 2719
• End Page: 2724
• Grant/Funding Information: This work was supported by grants from the NIH (NS036232 and NS101701, to XJL, and NS095279, to SHL) and the National Natural Science Foundation of China (grant 91332206).
• Keywords: BEHAVIORAL DEFICITS; MUTANT HUNTINGTIN; EARLY MOTOR; Research & Experimental Medicine; Neuroscience; NEURONS; DYSFUNCTION; Life Sciences & Biomedicine; Medicine, Research & Experimental; VIVO; RNA INTERFERENCE; NEUROPATHOLOGY; ABNORMALITIES; KNOCK-IN MICE; Science & Technology
• Research Categories: Biology, Genetics; Biology, Biostatistics; Biology, Neuroscience

Abstract

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.