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Mol Ther Nucleic Acids. 2019 Sep 6;17:829-839. doi: 10.1016/j.omtn.2019.07.009. Epub 2019 Jul 26.

CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington's Disease Mouse Model.

Author information

1
Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
2
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
3
Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
4
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA; Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; The Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA. Electronic address: schaffer@berkeley.edu.
5
Department of Bioengineering, University of Illinois, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL, USA. Electronic address: gaj@illinois.edu.

Abstract

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 ∼50% decrease in neuronal inclusions and significantly improved lifespan 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.

KEYWORDS:

AAV; CRISPR-Cas9; Huntington’s disease; gene therapy; genome editing

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