serval:BIB_18C9D3A78F11
The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes.
10.1016/j.celrep.2017.08.075
000411127400021
28930690
Merienne
N.
author
Vachey
G.
author
de Longprez
L.
author
Meunier
C.
author
Zimmer
V.
author
Perriard
G.
author
Canales
M.
author
Mathias
A.
author
Herrgott
L.
author
Beltraminelli
T.
author
Maulet
A.
author
Dequesne
T.
author
Pythoud
C.
author
Rey
M.
author
Pellerin
L.
author
Brouillet
E.
author
Perrier
A.L.
author
du Pasquier
R.
author
Déglon
N.
author
article
2017-09-19
Cell reports
2211-1247
journal
20
12
2980-2991
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.
Animals
Astrocytes/cytology
Astrocytes/metabolism
Base Sequence
CRISPR-Cas Systems/genetics
Cells, Cultured
Central Nervous System Diseases/genetics
Cerebral Cortex/cytology
Gene Editing
HEK293 Cells
Humans
Huntingtin Protein/genetics
Induced Pluripotent Stem Cells/cytology
Induced Pluripotent Stem Cells/metabolism
Kinetics
Mice
Neurons/cytology
Neurons/metabolism
CRISPR/Cas9
Huntington’s disease
KamiCas9
gene editing
lentiviral vectors
neurodegenerative diseases
self-inactivating system
eng
60_published
true
peer-reviewed
Publication types: Journal Article
Publication Status: ppublish
University of Lausanne
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