期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 17, 期 -, 页码 829-839出版社
CELL PRESS
DOI: 10.1016/j.omtn.2019.07.009
关键词
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资金
- Ruth L. Kirschstein National Research Service Award (NRSA) [F32GM113446]
- Judith and Jean Pape Adams Charitable Foundation
- NSF
- UC Berkeley Dissertation-Year Fellowship
- NIH [R01EY022975]
Huntington's disease (HD) is a currently incurable and, ultimately, fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene, which results in the production of a mutant protein that forms inclusions and selectively destroys neurons in the striatum and other adjacent structures. The RNA-guided Cas9 endonuclease from CRISPR-Cas9 systems is a versatile technology for inducing DNA double-strand breaks that can stimulate the introduction of frameshift-inducing mutations and permanently disable mutant gene function. Here, we show that the Cas9 nuclease from Staphylococcus aureus, a small Cas9 ortholog that can be packaged alongside a single guide RNA into a single adeno-associated virus (AAV) vector, can be used to disrupt the expression of the mutant HTT gene in the R6/2 mouse model of HD following its in vivo delivery to the striatum. Specifically, we found that CRISPR-Cas9-mediated disruption of the mutant HTT gene resulted in a similar to 50% decrease in neuronal inclusions and significantly improved life-span and certain motor deficits. These results thus illustrate the potential for CRISPR-Cas9 technology to treat HD and other autosomal dominant neurodegenerative disorders caused by a trinucleotide repeat expansion via in vivo genome editing.
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