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

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

Molecular Therapy: Nucleic Acids (Sep 2019)

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

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

Affiliations

Freja K. Ekman: Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
David S. Ojala: Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA
Maroof M. Adil: Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA
Paola A. Lopez: Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA
David V. Schaffer: 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; Corresponding author: David V. Schaffer, Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
Thomas Gaj: Department of Bioengineering, University of Illinois, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL, USA; Corresponding author: Thomas Gaj, Department of Bioengineering, University of Illinois, Urbana, IL, USA.

Journal volume & issue: Vol. 17
pp. 829 – 839

Abstract

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

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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