Giant Strides

First, thank you very much. Many of you have already read one or more accounts of the significant developments recently announced by Dr. Joel Gottesfeld at the Scripps Research Institute in La Jolla , California . You have also seen earlier announcements of other giant strides being made in this “treatment era” for Friedreich’s ataxia. These tremendously important breakthroughs would not have been possible if many of you had not made donations or helped raise funds to support the research, donated blood samples, participated in clinical trials, and kept actively aware via FAPG and INTERNAF of ways you could help.

In his work over the past three years, supported by FARA and NIH’s National Institute of Neurological Disorders and Stroke, Dr. Gottesfeld and his collaborators have advanced two exciting approaches to increasing the production of frataxin protein in FA patients to powerfully therapeutic levels. The approach you have been reading about most recently is the nearer-term prospect of the two. I wanted to try my hand at explaining in “our own words” as parents and patients what this extremely promising approach consists of, what it means to our community and what we will all need to do to help deliver on this promise.

What is the approach? We all know that FA results from genetic mutations on the frataxin gene. For about 96 percent of FA patients (all but those who have a point mutation), the mutation is a GAA triplet-repeat expansion on both frataxin genes (one from mom, one from dad). We also know that, because of such triplet-repeat expansions, the frataxin gene’s DNA code is transcribed, or read, far less often than normal so far less frataxin protein is produced.

Until recently, the leading explanation of how the triplet-repeat expansion impedes production of the frataxin protein has been that the long expansions fold back on themselves forming “sticky DNA” that does not allow the transcription molecule to break through very often to read the gene’s DNA code.

Dr. Gottesfeld decided to explore a different hypothesis. He knew that our genes and their DNA code are wrapped around bundles of proteins called chromatin. These various chromatin bundles, together, form the chromosomes. He knew, too, that when a particular gene is being read, the chromatin bundle is “relaxed” or uncondensed – so the gene is “unwrapped” - laid out for easy reading. The critical layer of chromatin proteins, called Histones, when they are in that “relaxed” mode, are “acetylated.” When the Histones are in their condensed mode, with the gene tightly wrapped around the chromatin and not available to be read, they have been “de-acetylated” by enzymes called de-acetylases.

So, Dr. Gottesfeld said, “Maybe the cell senses the triplet-repeat expansion in FA as a dangerous problem that should be “silenced” by recruiting de-acetylases to the Histones of the chromotin, keeping the chromatin condensed with the gene tightly wrapped around it and thus unreadable. Dr. Gottesfeld further said, “Let’s check as many of the known compounds called Histone Deacetylase (HDAC) inhibitors to see if any of them are able to “inhibit” de-acetylase enzymes, keeping them away from the Histones around which the frataxin gene is wrapped. He checked a lot of the known HDAC inhibitors and identified one that seemed to have at least some positive impact.

Dr. Gottesfeld and his fine lab team – funded primarily by FARA – then set about modifying the chemical composition of the promising HDAC inhibitor, attempting to optimize its positive effect. In other words, they tried to figure out which modified chemical structure would result in maximum translation or reading of the frataxin gene and maximum production of the frataxin protein. The lab has designed about twenty such modifications. The most effective of the modifications, when applied to cell cultures and white blood cells from FA patients and their family members, appears to increase frataxin protein production in the patient cells to levels that equal or exceed the levels in carrier family members.

What does this mean to the FA community? It means that we finally have our first promising, near-term prospect for increasing, in FA patients, their cells’ own production of frataxin protein to levels that should be significantly therapeutic. As Dr. Gottesfeld says in his own explanation and in the press release, we have a lot of work to do. Dr. Gottesfeld and his team and collaborators have a molecule that seems to be very promising in cell cultures and blood cells from FA families. This molecule is now being tested in FA mouse models. We will now need to have a certified facility make enough of this compound to “Good Manufacturing Practices” standards to be tested in significant quantities in healthy animals for toxicology (at what doses does it become toxic?) and for pharmaco-kinetics (where in the body does the molecule go?). The results and all the data from the animal model studies, the toxicology study and the pharmaco-kinetics study, along with a draft clinical trial protocol will then have to be presented to the FDA for approval of a clinical trial. Of course, enough of the “drug” will have to be made to conduct such a clinical trial.

You can probably imagine how expensive it will be to accomplish all the above. A reasonable estimate is probably $1.5M to $3M. And, as you all know, this extremely promising project – DR. Gottesfeld’s HDAC inhibitor - is one of five we all hope to have in clinical trials by next year. The Idebenone phase II trial was concluded this month at NIH and Dr. Nick Di Prospero hopes to publish the results within the next couple of months. A phase III Idebenone trial is being planned for the United States , having already opened in Europe . A small pilot study of EPO is underway in Austria . The phase II trial of MitoQ is targeted to begin this October. Edison Pharmaceuticals plans to begin the trial of its extremely promising compounds by early next year. In Dr. Gottesfeld’s message, he speaks of a clinical trial of his HDAC inhibitor beginning within about 18 months. By conventional standards, of course, that would be very quick. We all want to do it quicker. If we all pull together, we will.

Let me add that these five clinical trial candidates are not really in competition with one another – we are not looking ahead to a situation in which we are faced with a choice of one treatment from among the five. These compounds work in different ways and, in several cases, in different parts of the cell. In fact, we are hopeful that several of these potential therapeutics will prove to be beneficial and that their combined benefits in a “cocktail therapy” would exceed the benefits of any one of them acting alone.

No single organization can possibly accomplish all of this by itself. FARA has been working very hard to build and enhance an alliance of committed organizations that will accomplish all this by putting all their shoulders to the same wheel. You have probably seen the press release trumpeting the total commitment to partnership on the part of FARA and MDA, issued from MDA headquarters in Tucson , Arizona following the full-day FARA-MDA meeting there. We have all long known and benefited from the full collaboration between FARA and Seek A Miracle/MDA. You have also probably seen various press releases focused on the extremely fruitful collaborations we have established with the NIH, the world’s largest funding agency for medical research. FARA is eager to work in the same way with the National Ataxia Foundation to make our relationship another important part of this widening circle of full collaboration and co-funding.

Yes, that sounds like a pretty potent coalition, but it will not be successful unless all of us reading this message think hard about ways we can individually pitch in and help accomplish the mission of slowing, stopping and reversing the damage done by Friedreich’s ataxia. It will require help from each and every one of us because the pre-clinical studies needed to move from drug discovery through drug development (like for Dr. Gottesfeld’s HDAC inhibitor) and the clinical trials that follow are far more expensive than the basic research that has brought us this far. Now, several million dollars are needed to move from a drug discovery through clinical trial rather than tens of thousands of dollars to move through basic research toward a possible drug discovery.

Not everyone is going to be moved to organize a large fund-raising event. Some of you ARE organizing such events, though, and the month of September will see a number of them in locations from coast to coast across the United States . You can read about some of these upcoming events on the FARA website at http://www.faresearchalliance.org/news/index.asp#events

If you, your family and friends would like to help raise the funds we will need to cross the finish line together, you could send donations “in support of” one of these events – maybe the one being held closest to you. You could also ask people to make online credit-card donations on the FARA website at http://www.faresearchalliance.org/donations/

Those of you who have been in this group for a long time know that FARA has never made an appeal like this before. When we look, though, at the dramatic progress that is being made, the real prospects for treatments, and the costs associated with getting these potential treatments into and then through clinical trials, it is difficult to hold back any longer. Again, acting alone, there is little any of us can accomplish. Acting together, as we must do now more than ever, there is little we can NOT accomplish.

Giant Strides in “Treatment Era” for Friedreich’s Ataxia