Applying epigenetic modifying drugs to treat Friedreich's Ataxia

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We have recently shown that the GAA-triplet-repeat that pathologically expands and silences the frataxin (FXN) gene in the commonest autosomal recessive ataxia, Friedreich's Ataxia (FRDA), mediates transgene silencing in a manner reminiscent of chromatin-mediated silencing (Saveliev et al., 2003). This has led to the development of HDAC inhibitors (HDACis) which can upregulate frataxin (Festenstein, 2006; Herman et al., 2006) and are therefore potential treatments for this, as yet, untreatable and devastating condition. This proposal is to take forward a particular HDACi, known as compound z (due to patent restrictions), which we have found to be effective in up-regulating frataxin greater than 2-fold in lymphoblastoid cell lines and primary cells from patients with FRDA. Direct comparison with the HDACi, 4b, shows it to be more effective and it is certainly less toxic. As compound z has already been shown to have an excellent safety profile in humans and to cross the blood brain barrier, it has clear potential as a therapy for FRDA. We will now investigate its effects in humanised mouse models of FRDA. Thus, we will treat mice with the inhibitor and analyse the tissues that are characteristically affected by FRDA, such studies are clearly not possible in humans. Tissues will be analysed for FXN expression, FXN chromatin structure and for pathological changes. The mice will also be crossed to epigenetic-modifier mice to further dissect the mechanism of silencing and mechanism of action of this and other potential novel treatments at the chromatin/transcriptional level. FRDA can therefore be seen as a prototypic disease in which gene-silencing is the cause. We are well-placed to undertake this study as all the necessary techniques are already well established in the lab. Moreover, the CSC has a critical mass of researchers interested in epigenetics making this an ideal environment to pursue these studies. Compound z has a real possibility to become a treatment for FRDA, this study will go a long way to developing this potential.