CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model
| Autor: | Thomas Gaj, David S. Ojala, Paola A. Lopez, Freja K. Ekman, Maroof M. Adil, David V. Schaffer |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Huntington's Disease Huntingtin Mutant Clinical Sciences Biology Neurodegenerative Article 03 medical and health sciences Exon 0302 clinical medicine Rare Diseases Genome editing Huntington's disease Mutant protein Drug Discovery medicine Genetics genome editing Gene lcsh:RM1-950 Neurosciences AAV Gene Therapy medicine.disease gene therapy Cell biology Brain Disorders 030104 developmental biology lcsh:Therapeutics. Pharmacology 030220 oncology & carcinogenesis Neurological Molecular Medicine Biochemistry and Cell Biology CRISPR-Cas9 Trinucleotide repeat expansion Huntington’s disease Biotechnology |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 17, Iss, Pp 829-839 (2019) Molecular Therapy. Nucleic Acids Molecular therapy. Nucleic acids, vol 17 |
| ISSN: | 2162-2531 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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