Small molecules affecting transcription in Friedreich ataxia

Abstract

This review concerns the development of small molecule therapeutics for the inherited neurodegenerative disease Friedreich ataxia (FRDA). FRDA is caused by transcriptional repression of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin, and accompanying loss of frataxin protein. Frataxin insufficiency leads to mitochrondrial dysfunction and progressive neurodegeneration, along with scoliosis, diabetes and cardiomyopathy. Individuals with FRDA generally die in early adulthood from the associated heart disease, the most common cause of death in FRDA. While anti-oxidants and iron chelators have shown promise in ameliorating the symptoms of the disease, there is no effective therapy for FRDA that addresses the cause of the disease, the loss of frataxin protein. Gene therapy and protein replacement strategies for FRDA are promising approaches; however, current technology is not sufficiently advanced to envisage treatments for FRDA coming from these approaches in the near future. Since the FXN mutation in FRDA, expanded GAA·TTC triplets in an intron, does not alter the amino acid sequence of frataxin protein, gene reactivation would be of therapeutic benefit. Thus, a number of laboratories have focused on small molecule activators of FXN gene expression as potential therapeutics, and this review summarizes the current status of these efforts as well as the molecular basis for gene silencing in FRDA.

Missense Mutations Linked to Friedreich Ataxia Have Different but Synergistic Effects on Mitochondrial Frataxin Isoforms

“…These products have different biochemical properties and are thought to represent functionally different isoforms of human frataxin (15). In most Friedreich ataxia patients, large intronic GAA-repeat expansions silence FRDA expression (11,12) resulting in depletion of all mitochondrial FXN isoforms (15). In some patients there is only one expanded FRDA allele, whereas a single missense mutation is present on the other allele.…”

“…Our results have implications for Friedreich ataxia therapies. Although interventions that increase frataxin levels are suitable to reduce the gene silencing effect of a GAA expansion (11), compounds that specifically target stability, biogenesis, or catalytic function of FXN isoforms will be required to overcome the negative effects of I154F and W155R and probably other missense mutations as well. In general, our work emphasizes the potentially complex consequences of mutations in a multifunctional protein-frataxin being an excellent example among a growing number of such proteins (23).…”

Recognition of the DNA Minor Groove by Thiazotropsin Analogues

“…[34] The large effect caused by a relatively small molecule recognising short (6-8 bp) sequences of DNA has led to suggestions that, in order to improve the effectiveness of small-molecule interference with biological response processes, a synergistic approach could be used in which locally similar clusters of DNA structures or sequences could be targeted. [35][36][37] We considered whether mixtures of ligands could be used to target subtly different but related sequences at clusters of DNA recognition sites. Synergistic action between ligands might then exert wider, more efficient gene-silencing effects through allosteric activity.…”

Studies of Benzamide‐ and Thiol‐Based Histone Deacetylase Inhibitors in Models of Oxidative‐Stress‐Induced Neuronal Death: Identification of Some HDAC3‐Selective Inhibitors

“…For example, targeting HDAC3 in Friedreich's ataxia can correct the frataxin gene expression deficiency. [41] Conclusions In summary, we have synthesized a series of structurally unique benzamide-containing HDAC inhibitors that represent analogues of our previously reported highly potent phenylthiazolyl-and triazolylphenyl-bearing HDAC inhibitors. Some members of this class of benzamides were found to be reasonably selective for HDAC3 in isolated enzyme inhibition assays.…”