H4K16 constitute hallmarks of silent heterochromatin and are found immediately upstream and downstream of the GAA repat expansion in cells from FRDA patients. KIKI mice have similar changes, indicating that they are a suitable model for in vivo testing of treatments to alter histone modifications that may restore frataxin levels in FRDA. We chose a novel HDACI, compound 106, for testing in the animal model. 106 has 
been developed as an analog of the compound BML-210, the first HDACI shown to be effective in increasing acetylation levels at critical histone residues near the GAA repeat and in restoring frataxin levels in cultured cells from FRDA patients. In contrast, other common potent HDACIs, such as as suberoylanilide hydroxamic acid, suberoyl bishydroxamic acid, trichostatin A, and valproic acid do not increase FXN gene expression in cells from FRDA patients. The molecular basis for why these compounds are ineffective, as compared to the pimelic diphenylamides, exemplified by 106, is currently under investigation. We have established that 106 penetrates the blood-brain barrier and increases histone acetylation in the brain at a dose that causes no apparent toxicity in WT C57Bl/6 or in KIKI mice. This compound was able to restore normal frataxin levels in the Axitinib central nervous system and heart of KIKI mice, tissues that are relevant targets as they are involved in FRDA pathology. As no effect on frataxin levels was observed in similarly treated WT mice, we conclude that 106 directly interferes with the transcriptional repression mechanism triggered by the GAA repeat, which is thought to involve the induction of transcriptionally silent heterochromatin. Accordingly, the typical histone marks of heterochromatic regions that are present near the GAA repeat in KIKI mice were partially removed by BAY-60-7550 treatment with 106. In particular, acetylation increased with treatment at several lysine residues in histones H3 and H4, but no decrease in H3K9 trimethylation occurred. We propose that increased acetylation of H3K14 and of K5, K8 and K16 on H4, results in a more open, transcription permissive chromatin state despite persisting H3K9 trimethylation, because it interferes with binding of repressive proteins that recognize the trimethylated H3K9 mark, such as heterochromatin protein 1. Restoring frataxin expression represents an important step toward a treatment for FRDA if it is followed by functional recovery of affected cells. KIKI mice do not show overt pathology or abnormal behavior, but we identified changes in the overall gene expression profiles in relevant tissues that constitutes an observable, reproducible and biologically relevant phenotype as well as a biomarker to monitor the effectiveness of treatments. Remarkably, after 106 treatment gene expression profiles showed a clear trend toward normalization. This phenomenon cannot be considered a non-specific consequence of HDACI treatment, because the involved genes were not significantly modified in treated WT mice, whose frataxin levels also remained stable. Normalization of the transcription profile changes induced by lowered frataxin provides strong support to a possible efficacy of this or related compounds in reverting the pathological process in FRDA, at least as long as major cell loss has not occurred. Based on our results, potential therapeutics may be developed for FRDA, a so far incurable neurodegenerative disease. A distinctive group of diseases where amyloid deposition does not mainly occur in the central nervous system but rather in several organs in the periphery is associated to the plasma protein transthyretin. Amyloidosis linked to wild type TTR appears to cause senile systemic amyloidosis, whereas most of the one hundred TTR mutants, already identified, result in familial amyloidotic polyneuropathy. TTR binds and transports 15�C20% of serum thyroxine and up to 80% of thyroxine in central nervous system. In addition, TTR is the main carrier of vitamin A by forming a complex with retinol-binding protein.