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 antioxidants 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.

Figure 1

Structure of the DNA-binding molecule pentamidine. Taken from the PubChem data base (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4735).

Figure 2

Stereo view of an ensemble of 12 NMR structures of the complex of ImPyβImβImPyβDp (shown in gold) bound to 5'-AAAGAGAAG-3' (DNA in blue). Im = imidazole, Py = pyrrole, β = β-alanine, and Dp = dimethylaminopropylamide. The polyamide binds in the 3' to 5' orientation with respect to the N -> C direction of the ligand. The DNA geometry is fully B-type, with a narrow minor groove. Figure taken from (Urbach et al., 2002), with permission.

Figure 3

Polyamide structures and binding models. (A) Structures of polyamides FA1, FA2, FA3, FA5 and FA6, and the bodipy conjugate of FA1, FA1-Bodipy. Polyamides FA3, FA5, FA6 (ImPyβ(ImPyβ)₂₋₄ImβDp) are designed to target longer GAA·TTC repeats ([GAA]₄₋₆) as shown for FA3 in panel B. (B) Polyamide structures are represented schematically as binding models, with open circles representing Py; filled circles, Im; diamonds, β-alanine. Mismatches formed with polyamides FA2 and FA4 are indicated with shaded boxes. Figure adapted from (Burnett et al., 2006).

Figure 4

Structures of SAHA, BML-210 and 4b (Herman et al., 2006).

Figure 5

A model for reactivation of FXN transcription by histone deacetylase inhibitor 4b. HDACs deacetylate the amino terminal tails of the histones, promoting histone methylation at H3K9 and recruitment of heterochromatin proteins, resulting in FXN chromatin condensation and gene silencing. HDAC inhibitor 4b reverses silencing by inhibiting HDACs leading to histone acetylation by the action of associated histone acetyltransferases (HATs) and opening the chromatin domain containing the FXN gene. Taken from (Festenstein, 2006), with permission.