Researchers from Canada for the first time delivered CRISPR/Cas9 components with a single adeno-associated virus (AAV) into the heart of mice, enabling the deletion of the GAA repeat in the first intron of the FXN gene, which encodes frataxin.

The approach combined a small Cas9 nuclease (Campylobacter jejuni Cas9) with 2 single guide RNAs targeting the FXN gene (pre- and post-GAA) in the AAV vector (AAV9), which may offer several advantages in the context of Friedreich ataxia (FA) treatment.

“This interesting approach preserves the endogenous frataxin promoter and gene copy number, and the
correction is permanent. Correcting at least one allele should lead to cellular phenotype correction, and this treatment could be applicable to most of FA patients,” the researchers explained.

The researchers expect that the use of a single vector would allow an optimal expression of all system components, thereby maximizing gene editing efficiency while minimizing the dose of vector to be administered.

One month after injecting 2 mouse models of FA (YG8sR and YG8-800) with the AAV vector specifically produced to target the FXN gene, the researchers found the edited version of the gene in the heart and liver of the animals. The editing rates were slightly higher in the YG8sR mice compared to YG8-800 mice (4.7% vs 2.4% in the heart and 17.5% and 14.5% in the liver, respectively).

The FXN gene editing led to a significant increase of frataxin mRNA in the liver but not in the heart of YG8-800 mice. Furthermore, the editing rate was not sufficient to increase frataxin mRNA in YG8sR’s tissues.

The treatment showed no toxicity in mice, as confirmed by the similar weight between treated and control animals.


Yaméogo P, Gérard C, Majeau N, Tremblay JP. Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9. Gene Ther. Published online February 14, 2023. doi:10.1038/s41434-023-00387-0