Histone Deacetylases

Dr Joel Gottesfeld's lab in La Jolla, California (USA), is also working on heterochromatin modifiers as a potential treatment for FRDA, and Dr Gottesfeld started his talk by referencing a paper published by Richard Festenstein's group in 2003 (Nature) as the inspiration. His own work in California has supported the theory that heterochromatin gene silencing occurs in FRDA. The interaction between the active form of the frataxin gene and the inactive (silenced) form is mediated by enzymes called histone deacetylases (HDAC). To see if targeting these enzymes would result in an increase in frataxin, the researchers tested various commercially available HDAC inhibitors and found only one that was slightly active on the frataxin gene (compound BML-210). However they were then able to study derivatives of this compound and identified a compound (4B) which is active at increasing levels of frataxin mRNA and frataxin protein in cells. The next stage was to test the compound in a mouse model of FRDA, and they found that it was able to cross the blood brain barrier and enter the nervous system; it also inhibited HDAC in the brain. There are different classes of HDACs, based on whether they are zinc dependent or non-zinc dependent, and different HDAC inhibitors act on each of the different classes. It is important for research to identify which enzymes are the target, and this gives clues as to the desired chemical properties of the inhibitor. Chemical studies that his team has carried out have now suggested that the class 1 HDAC enzymes are the target for HDAC inhibitors which work on the frataxin gene, and they have identified HDAC3 as the primary target.


The pharmaceutical company Repligen is now working with the active HDAC inhibitors that have been identified, doing pharmacokinetic and toxicology studies to learn more and identify the most effective compounds. A library of derivatives that can be screened for potential treatments has been established, and toxicity studies are going well.

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