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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)829-839
Number of pages11
JournalMolecular Therapy - Nucleic Acids
Volume17
DOIs
StatePublished - Sep 6 2019

Fingerprint

Clustered Regularly Interspaced Short Palindromic Repeats
Huntington Disease
Trinucleotide Repeat Expansion
Neurodegenerative Diseases
Genes
Guide RNA
Technology
Dependovirus
Frameshift Mutation
Double-Stranded DNA Breaks
Endonucleases
Mutant Proteins
Staphylococcus aureus
Exons
RNA
Neurons
Gene Editing

Keywords

  • AAV
  • CRISPR-Cas9
  • Huntington's disease
  • gene therapy
  • genome editing

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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.

In: Molecular Therapy - Nucleic Acids, Vol. 17, 06.09.2019, p. 829-839.

Research output: Contribution to journalArticle

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. In: Molecular Therapy - Nucleic Acids. 2019 ; Vol. 17. pp. 829-839.
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