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

Ekman, Freja K.; Ojala, David S.; Adil, Maroof M.; Lopez, Paola A.; Schaffer, David V.; Gaj, Thomas

doi:10.1016/j.omtn.2019.07.009

Title: CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model

Journal Article · Fri Sep 06 00:00:00 EDT 2019 · Molecular Therapy - Nucleic Acids

DOI:https://doi.org/10.1016/j.omtn.2019.07.009· OSTI ID:1599809

Ekman, Freja K. ^[1]; Ojala, David S. ^[1]; Adil, Maroof M. ^[1]; Lopez, Paola A. ^[1]; Schaffer, David V. ^[1]; Gaj, Thomas ^[2]

Univ. of California, Berkeley, CA (United States)
Univ. of Illinois, Urbana, IL (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; R01EY022975

OSTI ID:: 1599809

Journal Information:: Molecular Therapy - Nucleic Acids, Vol. 17, Issue C; ISSN 2162-2531

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 60 works

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