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The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes
- Source :
- Cell reports, vol. 20, no. 12, pp. 2980-2991, Cell Reports, Vol 20, Iss 12, Pp 2980-2991 (2017)
- Publication Year :
- 2016
-
Abstract
- Neurodegenerative disorders are a major public health problem because of the high frequency of these diseases. Genome editing with the CRISPR/Cas9 system is making it possible to modify the sequence of genes linked to these disorders. We designed the KamiCas9 self-inactivating editing system to achieve transient expression of the Cas9 protein and high editing efficiency. In the first application, the gene responsible for Huntington’s disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease. Sequencing of potential off-targets with the constitutive Cas9 system in differentiated human iPSC revealed a very low incidence with only one site above background level. This off-target frequency was significantly reduced with the KamiCas9 system. These results demonstrate the potential of the self-inactivating CRISPR/Cas9 editing for applications in the context of neurodegenerative diseases.
- Subjects :
- Cerebral Cortex
Gene Editing
Neurons
Huntingtin Protein
Base Sequence
Induced Pluripotent Stem Cells
lentiviral vectors
self-inactivating system
Kinetics
Mice
KamiCas9
HEK293 Cells
lcsh:Biology (General)
Central Nervous System Diseases
Astrocytes
Animals
Astrocytes/cytology
Astrocytes/metabolism
CRISPR-Cas Systems/genetics
Cells, Cultured
Central Nervous System Diseases/genetics
Cerebral Cortex/cytology
Humans
Huntingtin Protein/genetics
Induced Pluripotent Stem Cells/cytology
Induced Pluripotent Stem Cells/metabolism
Neurons/cytology
Neurons/metabolism
CRISPR/Cas9
Huntington’s disease
gene editing
neurodegenerative diseases
CRISPR-Cas Systems
lcsh:QH301-705.5
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 20
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Cell reports
- Accession number :
- edsair.pmid.dedup....56c15e1b49448f78b5e48fc60d93d121