Journal
HUMAN GENE THERAPY
Volume 33, Issue 1-2, Pages 25-36Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2020.323
Keywords
Huntington's disease; gene editing; single nucleotide polymorphism
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Huntington's disease is a neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin gene. Inactivation of the mutant allele using CRISPR-Cas9 gene editing offers a potential therapeutic approach, and targeting a protein coding sequence containing a single nucleotide polymorphism allows for allele-specific inactivation. This study successfully demonstrated allele-selective reduction of mutant huntingtin protein in a mouse model of the disease.
Huntington's disease (HD) is a devastating, autosomal dominant neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Inactivation of the mutant allele by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 based gene editing offers a possible therapeutic approach for this disease, but permanent disruption of normal HTT function might compromise adult neuronal function. Here, we use a novel HD mouse model to examine allele-specific editing of mutant HTT (mHTT), with a BAC97 transgene expressing mHTT and a YAC18 transgene expressing normal HTT. We achieve allele-specific inactivation of HTT by targeting a protein coding sequence containing a common, heterozygous single nucleotide polymorphism (SNP). The outcome is a marked and allele-selective reduction of mHTT protein in a mouse model of HD. Expression of a single CRISPR-Cas9 nuclease in neurons generated a high frequency of mutations in the targeted HD allele that included both small insertion/deletion (InDel) mutations and viral vector insertions. Thus, allele-specific targeting of InDel and insertion mutations to heterozygous coding region SNPs provides a feasible approach to inactivate autosomal dominant mutations that cause genetic disease.
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