The genetic defect in Friedreich's ataxia (FRDA) is the expansion of a GAA·TCC triplet in the first intron of the FXN gene, which encodes the mitochondrial protein frataxin. Previous studies have established that the repeats reduce transcription of this essential gene, with a concomitant decrease in frataxin protein in affected individuals. As the repeats do not alter the FXN protein coding sequence, one therapeutic approach would be to increase transcription of pathogenic FXN genes. Histone posttranslational modifications near the expanded repeats are consistent with heterochromatin formation and FXN gene silencing. In an effort to find small molecules that would reactivate this silent gene, histone deacetylase inhibitors were screened for their ability to up-regulate FXN gene expression in patient cells and members of the pimelic 2-aminobenzamide family of class I histone deacetylase inhibitors were identified as potent inducers of FXN gene expression and frataxin protein. Importantly, these molecules up-regulate FXN expression in human neuronal cells derived from patient-induced pluripotent stem cells and in two mouse models for the disease. Preclinical studies of safety and toxicity have been completed for one such compound...Continue Reading
The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure
Inhibitory effects of expanded GAA.TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo.
Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich's ataxia
The GAA*TTC triplet repeat expanded in Friedreich's ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner
Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors
Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group
Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia
The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues
Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2)
Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription.
Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich's ataxia patients and in a mouse model.
Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model
Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich's ataxia.
A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model.
Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia.
Base excision repair of chemotherapeutically-induced alkylated DNA damage predominantly causes contractions of expanded GAA repeats associated with Friedreich's ataxia
Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming
Targeting HDAC3 Activity with RGFP966 Protects Against Retinal Ganglion Cell Nuclear Atrophy and Apoptosis After Optic Nerve Injury
Efficient electroporation of neuronal cells using synthetic oligonucleotides: identifying duplex RNA and antisense oligonucleotide activators of human frataxin expression
Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients
The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy
Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich's ataxia, and other rare iron-related diseases
Quantitative Proteomic and Network Analysis of Differentially Expressed Proteins in PBMC of Friedreich's Ataxia (FRDA) Patients
Role of frataxin protein deficiency and metabolic dysfunction in Friedreich ataxia, an autosomal recessive mitochondrial disease
A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis.
Structure-function analysis of the conserved tyrosine and diverse π-stacking among class I histone deacetylases: a QM (DFT)/MM MD study
Quantitative proteomic analysis identifies targets and pathways of a 2-aminobenzamide HDAC inhibitor in Friedreich's ataxia patient iPSC-derived neural stem cells
Ataxia is a neurological condition characterized by lack of voluntary coordination of muscle movements including loss of coordination, balance, and speech. Discover the latest research on different types of ataxias here.