Original Article

Gene Therapy (2017) 24, 265–274; doi:10.1038/gt.2016.89; published online 19 January 2017

Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich ataxia

D L Ouellet1,2, K Cherif1,2, J Rousseau1,2 and J P Tremblay1,2

  1. 1Centre de Recherche, Centre Hospitalier, Universitaire de Québec, Quebec City, QC, Canada
  2. 2Département de Médecine Moléculaire, Faculté de Médecine, CHU de Québec, Université Laval, Québec City, QC, Canada

Correspondence: Dr JP Tremblay, Department of Molecular Medicine, Faculté de Médecine, CHU de Québec, Laval University, CR-CHUQ, 2705 Laurier Boulevard, Room P-09300, Quebec City, QC, Canada G1V 4G2. E-mail: jacques-p.tremblay@crchul.ulaval.ca

Received 8 November 2016; Accepted 19 December 2016
Accepted article preview online 26 December 2016; Advance online publication 19 January 2017

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Abstract

The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo. Nevertheless, our results suggest the YG8sR as a better and more suitable model for the study of the CRISPR-Cas9 edition of the mutated frataxin gene.