Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9

Pouiré Yaméogo, Catherine Gérard, Nathalie Majeau & Jacques P. Tremblay. Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9. Gene Ther (2023). doi:10.1038/s41434-023-00387-0

We are therefore aiming to develop FRDA treatment based on the deletion of GAAr with CRISPR/Cas9 technology using a single AAV expressing a small Cas9 (CjCas9) and two single guide RNAs (sgRNAs) targeting the FXN gene. This AAV was intraperitoneally administrated to YG8sR (250–300 GAAr) and to YG8-800 (800 GAAr) mice. DNA and RNA were extracted from different organs a month later. PCR amplification of part of intron 1 of the FXN gene detected some GAAr deletion in some cells in heart and liver of both mouse models, but the editing rate was not sufficient to cause an increase in frataxin mRNA in the heart. However, the correlation observed between the editing rate and the distribution of AAV suggests a possible therapy based on the removal of the GAAr with a better delivery tool of the CRISPR/Cas9 system.