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CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease
Su Yang, … , Shihua Li, Xiao-Jiang Li
Su Yang, … , Shihua Li, Xiao-Jiang Li
Published June 19, 2017
Citation Information: J Clin Invest. 2017;127(7):2719-2724. https://doi.org/10.1172/JCI92087.
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Brief Report Neuroscience

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

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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.

Authors

Su Yang, Renbao Chang, Huiming Yang, Ting Zhao, Yan Hong, Ha Eun Kong, Xiaobo Sun, Zhaohui Qin, Peng Jin, Shihua Li, Xiao-Jiang Li

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Figure 2

Behavioral analysis of heterozygous HD140Q-KI mice with depletion of neuronal HTT in the striatum by AAV-HTT-gRNA/AAV-MECP2-Cas9 injection.

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Behavioral analysis of heterozygous HD140Q-KI mice with depletion of neu...
(A) Schematics showing the viral vectors used. HA, human influenza hemagglutinin; ITR, inverted terminal repeat; KASH, Klarsicht, ANC-1, Syne Homology; WPRE, woodchuck hepatitis virus post-transcriptional regulatory element. (B) Double immunostaining with anti–DARRP-32 indicated that medium spiny neurons expressed AAV-HTT-gRNA. Scale bar: 10 μm. (C) Motor functions of heterozygous HD140Q-KI mice injected with AAV-HTT-gRNA/AAV-MECP2-Cas9 (KI HTT-gRNA) or AAV-control-gRNA/AAV-MECP2-Cas9 (KI control-gRNA) and WT mice injected with AAV-control-gRNA/AAV-MECP2-Cas9 (WT) were evaluated using rotarod, balance beam, and grip strength tests at different time points after injection (n = 12 for each group; *P < 0.05, **P < 0.012, and ***P < 0.001, by 2-way ANOVA with Bonferroni’s test, comparing the KI HTT-gRNA group with the KI control-gRNA group).Data represent the mean ± SEM.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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