Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia

Abstract

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 and a phase I clinical trial in FRDA patients has been initiated. Furthermore, medicinal chemistry efforts have identified improved compounds with superior pharmacological properties.

Keywords: Friedreich's ataxia; heterochromatin; histone deacetylase inhibitor; neurodegenerative disorder.

Figure 1. Putative silencing pathway in Friedreich's ataxia

Figure first published in and modified from Festenstein (2006).

Figure 2

Structures of the histone deacetylase inhibitors.

Figure 3

Compounds with improved pharmacological properties. (A) Brain penetration can be improved by elimination of the left amide, and replacement with an ether, olefin, or ketone. Metabolic stability can be improved by introducing a non-saturated α/β linkage adjacent to the right amide, which prevents formation of a benzimidazole. (B) Synthetic route to compounds with these replacements using Cu(I)-catalyzed click chemistry, where azide A is reacted with alkyne B, and after Boc deprotection, a triazole is generated in the linker region of the histone deacetylase inhibitor.