Friedreich's Ataxia (FRDA) is the most prevalent form of hereditary ataxia. Most individuals with FRDA have large expansions of “GAA/TTC” triplets in the first intron of the FRATAXIN (FXN) gene. These repeat expansions repress FXN transcription resulting in reduced levels of mature FXN protein when compared with unaffected individuals. It has been proposed that the presence of expanded GAA/TTC repeats is associated with heterochromatin-like changes at the FXN locus. With no cure for the disease, currently patients with FRDA undergo symptom management. Number of approaches including gene therapy are being attempted around the world to mitigate the loss of FXN expression to improve the disease condition. However, none have led to clear pathway to treatment suggesting missing links in the molecular aetiology of the disease. Our group have discovered a repeat expansion-associated growth defect in a plant model and have been using this model to decipher molecular mechanisms that govern repeat expansion-associated epigenetic silencing. Here we report our exploitation of the findings in plants to FRDA cell lines. We have been able to test the roles for some of the candidate genes discovered through the plant system in FRDA cells. In addition, we report our findings on a genome-wide CRISPR screen and reveal novel genes and mechanisms that could be potentially targeted for FRDA treatment. Our genome wide perturbation study has the potential to lead to significant advancement towards addressing FRDA disease.