HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model

Abstract

BackgroundFriedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAA⋅TTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4.Methodology/Principal FindingsBy chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)230 repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels.Conclusions/SignificanceLack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.

Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors

“…These positive data were supported by other studies using in vivo models, with most mice responding favorably to treatment protocols incorporating HDACi (29,37).…”

Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome

“…Recently, mouse models for spinocerebellar ataxia 1 and Friedreich ataxia have led to potential drug targets and clinical trials. 4,5 In the future, this zebrafish model may also be used to understand the function of C19L1, analyze and confirm cell experiments, and ultimately test potential therapies for this form of ataxia.…”

“…Identifying additional recessive ataxia genes may help in diagnosis and prognosis and the identification of novel ataxia pathways, 3 which in turn may lead subsequently to novel drug development. 4,5 Next-generation sequencing has recently been used to identify genes involved in rare neurologic disorders, 6 including ataxia, 2,7-9 often with the help of consanguinity, 2 as homozygosity further narrows down the linkage evidence, 10 and homozygous mutations are easier to detect than 2 compound heterozygotes. Here, we identified a novel splice mutation by next-generation sequencing and homozygosity mapping in a small consanguineous family that leads to ataxia, developmental delay, and mental retardation in humans, and abnormalities in cerebellar morphology and movement in a zebrafish model with the same splicing defect.…”

The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

“…Toxicity studies of various HDAC inhibitors, including SAHA, have demonstrated widespread effects in human cancer cells in vitro, including activation of proapoptotic and inhibition of antiapoptotic pathways, stimulation of cell differentiation, and induction of growth arrest (20)(21)(22). These features have led to the approval of SAHA for use in human cancer clinical trials (22); however, such properties might be expected to exacerbate symptoms in neurodegenerative disorders, such as HD.We have developed a class of benzamide-type HDAC inhibitors that show promising results in Friedreich's ataxia disease models (23,24). These compounds are structurally related to the well-known HDAC inhibitor SAHA but are not hydroxamic acids and, unlike SAHA, were found to increase expression of the frataxin gene in lymphocytes from Friedreich's ataxia patients (23).…”

“…We have developed a class of benzamide-type HDAC inhibitors that show promising results in Friedreich's ataxia disease models (23,24). These compounds are structurally related to the well-known HDAC inhibitor SAHA but are not hydroxamic acids and, unlike SAHA, were found to increase expression of the frataxin gene in lymphocytes from Friedreich's ataxia patients (23).…”