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

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

Publication date: Sep 06, 2019

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.

Open Access PDF

Ekman, F.K., Ojala, D.S., Adil, M.M., Lopez, P.A., Schaffer, D.V., and Gaj, T. CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model. 06671. 2019 Mol Ther Nucleic Acids (17):

Concepts Keywords
Autosomal Dominant Human Nature
Cas9 Huntingtin
CRISPR Genome editing
Endonuclease CRISPR
Exon Enzymes
Frameshift Cas9
Gene Biotechnology
Genome Editing Immune system
Huntingtin Life sciences
Huntington Genetic engineering
Mutant Branches of biology
Neurodegenerative Disorder
Neurodegenerative Disorders
Neurons
Nuclease
Nucleic
Ortholog
RNA
Staphylococcus Aureus
Striatum
Vector
Virus

Semantics

Type Source Name
gene UNIPROT SLC6A4
gene UNIPROT HTT
disease MESH trinucleotide repeat expansion
disease MESH neurodegenerative disorder

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