CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo.
CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo.
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DOI：
10.1016/j.ymthe.2016.11.010
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发表时间：
2017-01-04
期刊：
影响因子：
--
通讯作者：
Davidson BL
中科院分区：
文献类型：
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作者：
Monteys AM;Ebanks SA;Keiser MS;Davidson BL
Huntington disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by CAG repeat expansion (>36 repeats) within the first exon of the huntingtin gene. Although mutant huntingtin (mHTT) is ubiquitously expressed, the brain shows robust and early degeneration. Current RNA interference-based approaches for lowering mHTT expression have been efficacious in mouse models, but basal mutant protein levels are still detected. To fully mitigate expression from the mutant allele, we hypothesize that allele-specific genome editing can occur via prevalent promoter-resident SNPs in heterozygosity with the mutant allele. Here, we identified SNPs that either cause or destroy PAM motifs critical for CRISPR-selective editing of one allele versus the other in cells from HD patients and in a transgenic HD model harboring the human allele. Monteys and colleagues show that CrispR/Cas9 editing can reduce expression of the mutant huntingtin allele in human cell lines from Huntington’s disease patients and in the brains of a mouse model of Huntington’s disease, advancing the therapeutic utility of genome editing for this and other dominantly inherited CNS disorders.
