A hypertrophic cardiomyopathy, present in most cases, may become symptomatic and even cause premature death. Other common problems include kyphoscoliosis, pes cavus, and, in 10 % of patients, diabetes mellitus. FRDA is caused by partial deficiency of the mitochondrial protein frataxin. Though the function of GANT61 frataxin is still partly controversial, there is general agreement that it is involved in cellular iron homeostasis and that its deficiency results in multiple enzyme deficits, mitochondrial dysfunction and oxidative damage. Frataxin binds ferrous iron through negatively charged amino acids on its surface, it promotes the mitochondrial synthesis of ironcontaining molecules, in particular iron-sulfur clusters and heme, and it controls the ability of iron to perform redox chemistry. Frataxin deficiency significantly affects ISC synthesis and results in reduced activities of several enzymes that require ISCs as prosthetic groups. Frataxin may also have a more general protective effect against oxidative stress and in determining antioxidant responses, even in the absence of excess iron. Complete absence of frataxin is incompatible with life in higher organisms, as demonstrated by the embryonic lethality observed in systemic gene knock-out models and by the eventual loss of cells targeted for frataxin gene deletion in conditional knock-out models. The human disease is caused by the pathological hyperexpansion of a GAA?TTC repeat sequence, ranging from 60�C1700 repeats, in the first intron of the frataxin gene that partially suppresses FXN gene expression. This WY 14643 50892-23-4 mutation is present at the homozygous state in most patients and in compound heterozygosity with a different loss-of-function mutation in a small minority of cases. In FRDA patients, frataxin amounts vary between 5% and 30% of those of normal individuals, and are little more than 50% of normal in heterozygous FRDA carriers, who have no sign of disease. These findings suggest that restoring FXN gene expression in FRDA patients to heterozygote levels may substantially slow the course of the disease. In order to develop treatments to reduce or eliminate FXN transcriptional silencing, it is necessary to understand the underlying mechanisms. In vitro and in bacterial plasmids, pathological lengths of GAA repeats adopt a non-B, triple helical DNA structure that blocks and sequesters the advancing RNA polymerase. The same repeats, when linked to a reporter gene in transgenic mice and in cells from FRDA patients, become associated with transcriptionally silent heterochromatin. Therefore, decondensing the chromatin structure at the GAA repeat expansion appears an appealing target for FRDA therapeutics. Since deacetylated histones are generally associated with silent heterochromatin, HDAC inhibitors have the potential to make heterochromatin revert to an open, active conformation that allows gene expression. The increase in FXN transcription is accompanied by increased acetylation of histone H3 at lysine14, as well as at H4K5 and H4K12 near the GAA repeat. As a further step to evaluate these drugs as potential FRDA therapeutics,we have nowinvestigated the efficacyand acutetoxicity of a compound from this novel family of HDACI in a FRDA mouse model. Our data indicate that in a mouse model that carries expanded GAA repeats in the endogenous frataxin gene, a member of this class of HDACI is able to restore frataxin levels and the gene expression profile to those of wild-type mice. In the present study we have demonstrated the in vivo feasibility of a therapeutic approach to activate the FXN gene in a mouse model that recapitulates the genetic and epigenetic features of FRDA. Previous work has shown that FXN silencing in FRDA is likely to be the consequence of chromatin changes induced by the expanded intronic GAA repeat. Post-translational modifications of histone tails are thought to form a code, called the histone code, that affect gene expression by providing binding sites for proteins involved in controlling chromatin condensation and transcription.