Histone Deacetylase Inhibitors (HDACi)

Histone deacetylase inhibitors (HDACi) are small molecules or compounds that activate the expression of genes by inhibiting the activity of enzymes called histone deacetylases (HDACs).

HDACs are proteins that help remove the acetyl group from histones, which are positively-charged proteins that interact strongly with the negatively-charged DNA, causing it to be tightly packed as a condensed structure, preventing the expression of genes. [Here, “gene expression” refers to the process through which a gene is “read” and a protein produced based on that information.] The addition of an acetyl group — essentially what HDACi allow to happen — neutralizes the positive charge on histones, weakening their interaction with the DNA. This relaxes the condensed structure and allows for gene expression.

HDACi, in other words, block the deacetylation of histones, causing an increase in their acetylated form. This relaxes the structure of DNA and increases gene expression.

HDACi in Friedreich’s ataxia

The defect in the FXN gene (an abnormal expansion of GAA repeats) that causes Friedreich’s ataxia (FA) resides within the non-coding part of the gene, which undergoes epigenetic changes such that the expression of the gene is silenced or “switched off,” resulting in inadequate amounts of the frataxin protein being produced. Epigenetic changes refer to the addition or removal of chemical groups, such as acetyl or methyl groups, onto the histones or the DNA. In the case of FA, epigenetic changes include histone deacetylation (removal of the acetyl group from histones), DNA methylation (addition of a methyl group to the DNA), and histone trimethylation (addition of three methyl groups to the histone).

HDACi could be used in FA to reverse gene silencing by inhibiting the removal of acetyl groups, allowing the gene to be expressed, potentially restoring optimal levels of frataxin protein.

Several inhibitors have been developed for HDACs that belong to different chemical classes, and some are seen to increase frataxin mRNA and protein levels.


Researchers identified a class of compounds, called 2-aminobenzamides, that inhibit HDACs. Those that belong to class 1, particularly, were shown to activate the expression of the frataxin gene in mouse models and in laboratory-grown cells derived from FA patients.

These compounds are thought to be fairly safe because they exert their effect only on the defective gene, and trigger mostly minor changes in other genes. Their safety has also been confirmed in animal experiments. These compounds also exhibit long-lasting effects through a slow dissociation from their target. Among different classes of HDAC inhibitors, 2-aminobenzamides show the most promise as a potential FA treatment.

A lead candidate in this class — called RG2833 — was identified by the bioprocessing company Repligen. Long-term application of RG2833 in mouse models and in cells derived from FA patients increased histone acetylation in the FXN gene and increased frataxin protein levels. It also improved coordination in FA mouse models without toxic side effects.

RG2833 has also been tested in a small Phase 1b clinical trial in 20 FA patients. The trial, which ended in April 2013, was designed to study the safety and optimal dose of the drug. Four cohorts of FA patients who were given single doses of the drug (escalating among cohorts from 30 mg per day to 240 mg per day) and monitored over four in-hospital days using various blood and biophysical tests. In the third and fourth cohorts, which were given the highest dose levels, the treatment was well-tolerated and an increase in frataxin mRNA (a measure of frataxin gene expression) was reported. These results were significant in that they provided proof that an HDACi delivered orally (in pill form) could increase frataxin gene expression. The drug did not cause any adverse events.

However, RG2833 could not advance in clinical trials allowing for longer term exposure, due to its poor distribution in the brain and spinal cord and its potential to break down into possibly toxic or cancer-causing metabolites. Modifications of this compound were needed before further clinical development could take place.

Using medicinal chemistry, the structural features of RG2833 were modified to improve its brain distribution and metabolic stability. The new compound, called click-1 (for Cu(I)-catalyzed click chemistry), showed comparable activity to RG2833 in nerve cells derived from patients in inducing the expression of the FXN gene, along with improved brain penetration and stability. Based on these findings, new generations of molecules have been synthesized and are now being tested in preclinical studies.


Nicotinamide (vitamin B3) is another HDACi found to be effective in preclinical FA models. It has also been tested in clinical trials.

In an open-label, dose-escalation study (NCT01589809), patients with FA were given escalating doses of nicotinamide ranging from 2 to 8 g, in both single and multiple doses, over periods of up to eight weeks. Results showed that higher doses of nicotinamide increased FXN expression and reduced repressive histone modifications in the gene, but failed to establish any clinical benefit. High doses of the vitamin triggered nausea in all patients and vomiting in half of those given the highest doses. These side effects may be attributed to non-specific effects of nicotinamide on FXN gene expression, which was increased in both normal and defective genes.

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