CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model
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.
- Authors:
-
- Univ. of California, Berkeley, CA (United States)
- Univ. of Illinois, Urbana, IL (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)
- OSTI Identifier:
- 1599809
- Grant/Contract Number:
- AC02-05CH11231; R01EY022975
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecular Therapy - Nucleic Acids
- Additional Journal Information:
- Journal Volume: 17; Journal Issue: C; Journal ID: ISSN 2162-2531
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; CRISPR-Cas9; Huntington's disease; AAV; gene therapy; genome editing
Citation Formats
Ekman, Freja K., Ojala, David S., Adil, Maroof M., Lopez, Paola A., Schaffer, David V., and Gaj, Thomas. CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model. United States: N. p., 2019.
Web. doi:10.1016/j.omtn.2019.07.009.
Ekman, Freja K., Ojala, David S., Adil, Maroof M., Lopez, Paola A., Schaffer, David V., & Gaj, Thomas. CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model. United States. https://doi.org/10.1016/j.omtn.2019.07.009
Ekman, Freja K., Ojala, David S., Adil, Maroof M., Lopez, Paola A., Schaffer, David V., and Gaj, Thomas. Fri .
"CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model". United States. https://doi.org/10.1016/j.omtn.2019.07.009. https://www.osti.gov/servlets/purl/1599809.
@article{osti_1599809,
title = {CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model},
author = {Ekman, Freja K. and Ojala, David S. and Adil, Maroof M. and Lopez, Paola A. and Schaffer, David V. and Gaj, Thomas},
abstractNote = {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.},
doi = {10.1016/j.omtn.2019.07.009},
journal = {Molecular Therapy - Nucleic Acids},
number = C,
volume = 17,
place = {United States},
year = {Fri Sep 06 00:00:00 EDT 2019},
month = {Fri Sep 06 00:00:00 EDT 2019}
}
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Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification
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Rational design of highly active sgRNAs for CRISPR-Cas9–mediated gene inactivation
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