The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes.

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.

DOI: 10.1016/j.celrep.2017.08.075

Cite this paper

@article{Merienne2017TheSK, title={The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes.}, author={Nicolas Merienne and Gabriel Vachey and Lucie de Longprez and C{\'e}cile Meunier and Virginie Zimmer and Guillaume Perriard and M. Luisa Gonz{\'a}lez de Canales and Amandine Mathias and Lucas Herrgott and Tim Beltraminelli and Axelle Maulet and Thomas Dequesne and Catherine Pythoud and Mar{\'i}a del C. Rey and Luc Pellerin and Emmanuel Brouillet and Anselme L. Perrier and Renaud A. Du Pasquier and Nicole Deglon}, journal={Cell reports}, year={2017}, volume={20 12}, pages={2980-2991} }