There are a number of challenges in each of these potential applications of HDAC inhibitors. First, humans have about 18 of the Histone DeACetylase (HDAC) enzymes the HDAC inhibitors are intended to inhibit. Each of these HDAC enzymes do different things to different genes. The first important step in this direction for FA scientists was determining that HDAC enzymes were responsible for "silencing" the FA gene -- the "silencing" that resulted in the FA gene producing far less of the frataxin protein. The second step was determining which of the 18 HDAC enzymes or which combination of those enzymes was the culprit in FA. Dr. Gottesfeld appears to have taken that second step, thus setting the target for the third step, which is the toughest by far - determining the structure of the HDAC inhibitor that is most effective in inhibiting the culprit HDAC. Furthermore, the HDAC inhibitor we design and select must be effective in inhibiting the culprit HDAC enzyme from "silencing" the FA gene while not causing any damage to any other genes elsewhere.

This design, test and select process is very complicated. Dr. Gottesfeld initiated this process by testing in FA cells all the HDAC inhibitors "on the shelf." He found that many of the inhibitors had no effect on the FA gene's expression of frataxin protein, while others actually reduced the amount of protein produced. With one HDAC inhibitor, though, he saw a slight increase in frataxin protein expressed by the FA gene. He looked closely at the structure of that HDAC inhibitor and began the "design" phase, modifying the structure in various ways and looking for maximum inhibition of the target HDAC enzyme and maximum increases in frataxin protein production. When Repligen licensed the "discovery" from The Scripps Research Institute, the company accelerated this "design" process and, along with Dr. Gottesfeld, has now designed a "library" of different structures (about 150 of them or so) they have tested in FA cells for maximum positive effect on the FA gene and minimum negative effect elsewhere. The inhibitors that showed most promise in the FA cells have been tested in the FA mice and the "winner" has become RG-2833, the lead candidate that has been submitted to the FDA and discussed with the EMEA (European Medicine Agency - the FDA equivalent in Europe).

While Repligen is advancing RG-2833 as the lead candidate in FA, like any good drug company, they are working hard on a follow-on candidate in hopes of developing a compound that might be even better.  FARA, MDA, GoFAR and Ataxia UK (hope I'm not leaving anybody out) all helped support the Scripps and Repligen development of the lead candidate.  FARA and GoFAR have provided a half-million dollars recently to help develop the follow-on candidate, and Scripps-Repligen have applied to the NIH for additional funding of that effort.

So, although there are a number of HDAC inhibitors that have been used in a few other conditions and a good number of HDAC inhibitors in clinical trials already (mostly cancer), the HDAC inhibitors being designed, tested and selected specifically for FA are new structures, new compounds, New Chemical Entities, unique to FA and subject to FDA and EMEA's consideration as such.  While this process is taking time, we can see why it is so important.  As Dr. Gottesfeld's early experiments showed, most of the HDAC inhibitors that were on the shelf when he started would have either harmed our FA patients or, at best, would have provided no benefit.  The glimmer of hope provided by one of those inhibitors, after an intensive design, test and select process, is now becoming a bright beacon of hope for all of us.  

Again, Repligen's plan is to conclude the FDA-required animal studies and submit the additional data to the Agency so as to have a decision by early in 2011 as to how and where to commence the clinical trials of the FA HDAC inhibitors as soon as possible during the year.

Hope that helps,

Ronald J. Bartek
Friedreich's Ataxia Research Alliance (FARA)
P. O. Box 1537
Springfield, VA 22151
Tel (703) 426-1576
FARA website:
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

The legacy of Marie Schlau: literature to help cure Friedreich's Ataxia

If you feel like reading an unputdownable novel while collaborating with a just and solidary cause, "The Legacy of Marie Schlau" is your book! 100% of all funds raised will be dedicated to medical research to find a cure for Friedreich's Ataxia, a neurodegenerative disease that affects mostly young people, shortening their life expectancy and confining them to a wheelchair.

The life of Marie Schlau, a German Jewish girl born in 1833 hides great unsolved mysteries: accidents, disappearances, enigmas, unknown diagnoses, disturbing murders, love, tenderness, greed, lies, death ... alternatively a different story unfolds every time and takes us closer to the present. Thus, there are two parallel stories unravelling, each in a different age and place, which surprisingly converge in a revelatory chapter.

Paperback and Kindle versions for "The legacy of Marie Schlau" available for sale at Amazon now!


Research projects currently being financed by BabelFAmily

Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:

1) Gene Therapy for Friedreich's Ataxia research project:

The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.

2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.

The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.



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