In February 2003, FARA and NIH again collaborated to fund, organize, and co-host the second international Friedreich's ataxia (FRDA) scientific research conference at NIH in Bethesda, Maryland, outside Washington, D.C. About 100 scientists from 12 different countries came together to compare findings, share insights, and chart the course ahead in the search for treatments and a cure for FRDA. A great deal was accomplished across what became a five-day conference. FARA held its first scientific conference at NIH in 1999 and much of the 2003 conference evolved from that earlier workshop. FRDA researchers say this is one of the fastest tracks they have ever seen in medical research. FRDA research moved from gene discovery to promising clinical trials in only seven years. Another way to characterize advances in FRDA research is found in the statement, "In Friedreich's ataxia, we are entering the treatment era" (Dr. Robert Wilson, Chairman, FARA Scientific Review Committee, March 2002, NAF Annual Meeting). This extremely positive milestone has been achieved because of the advances made in the science of the disease since the FRDA gene was identified in 1996 by a team led by Dr. Massimo Pandolfo, who also serves on FARA's Board of Directors and its Scientific Review Committee. Since the gene discovery, scientists have identified the protein expressed by the FRDA gene. The protein has been named Frataxin, after the disorder, and FRDA scientists have determined that the protein performs its function at the walls of the mitochondria (the energy factories of our cells). The scientists have also determined that the large numbers of GAA triplet repeats on the affected copies of the FRDA gene cause the "double helix" of the gene to fold back onto itself and form a triplex (or "sticky DNA") on the gene structure so that the gene's code is often not effectively read and much less of the protein is produced. The scientists have further determined that, in people diagnosed with FRDA, the shortage of the Frataxin protein results in significant reduction in energy production by the mitochondria, excessive "free radicals" that cause oxidative stress, and excessive iron accumulations in the mitochondria. As a consequence, the cell is progressively damaged and eventually dies. Scientists have also discovered that FRDA can be caused by a point mutation. In a small number of patients (about 5%), one of the FRDA genes manifests the classic GAA triplet repeats while the other carries a single-nucleotide mutation. In some cases, these are mutations in which one nucleotide appears in a position normally occupied by a different nucleotide. In other cases, called "frameshift" mutations, one additional nucleotide is inserted or one normal nucleotide is deleted, thus shifting the transcription of triplets. These single "misspellings" in the FRDA gene's code disrupt the transcription of protein-forming instructions. So, much has been learned about the FRDA gene since its identification in 1996, and knowledge about the Frataxin protein has grown at a similar rate. We know, for example, that a total absence of Frataxin is inconsistent with life. Mouse embryos in which both FRDA genes have been eliminated ("knocked out") and in which, therefore, no Frataxin protein is produced, die in embryo. We know that the Frataxin protein operates within the mitochondria. We know that Frataxin is important in the formation of the iron-sulfur clusters that play an essential role in the mitochondria's production of energy. When normal levels of Frataxin are available, we see that excess iron does not build up in the mitochondria, that iron remains in its plus-2 state (Fe+2) and combines properly with sulfur to form iron-sulfur clusters. When sufficient Frataxin protein is not available, it appears that iron oxidizes, gives up an electron, transitions to Fe+3, and contributes to the production of the free radicals that damage cells. We also know which 210 amino acids form the Frataxin protein and in what order they are assembled. jump to top Antioxidation
FRDA scientists are impressed with the potential for antioxidant therapies. Antioxidants some natural and some synthetic are compounds that bind up free radicals and reduce the oxidative stress that damages cells. Some of the best known antioxidants of interest in FRDA are Idebenone, Coenzyme Q10 (CoQ10), Vitamin E, Selenium, Alpha Lipoic Acid, N-Acetyl-L-Cysteine (NAC), green tea, green leafy vegetables, and darkly pigmented fruits like blueberries. "The apparent benefit of lipid-soluble antioxidants for the cardiomyopathy in FRDA, suggests a substantial capacity for renewal of damaged mitochondria. Perhaps if reactive oxygen species in FRDA mitochondria are sufficiently neutralized by lipid-soluble antioxidants, mitochondrial repair processes gain the upper hand over the chronic oxidative damage to mitochondria that apparently underlies the disease." (Dr. Robert Wilson, University of Pennsylvania) One of the most exciting briefings at FARA's 1999 workshop was given by the French team led by Drs. Rustin, Rotig, and Munnich. The briefing dealt with the team's "open-label" (as opposed to double-blinded, placebo controlled) trial in which FRDA patients were given an antioxidant called Idebenone, a synthetic compound similar to but smaller than the naturally found Coenzyme Q10. The impact of the drug, as reported by the French team, was that the hypertrophic cardiomyopathy of the patients was reduced significantly. The French trial was followed by double-blinded, placebo-controlled trials of Idebenone in a number of other countries. jump to top Drug Trials Mark "Treatment Era"
These initial Idebenone trials used a very small dose, usually 5 miligrams per kilogram of body weight (5 mg/kg), with some going to 10 mg/kg. They demonstrated that Idebenone does seem to reduce cardiac hypertrophy significantly (5%-20 %). At these low doses, however, there was no convincing evidence of any benefit in terms of the neurological symptoms the ataxia. A team led by Dr. Rob Wilson and his colleagues at NIH's National Institute of Neurological Disorders and Stroke (NINDS), and supported by FARA, set out to conduct a large U.S. trial to prove safety and efficacy of Idebenone in FRDA so the drug could be approved for FRDA by the U.S. Food and Drug Administration (FDA). The drug could then be prescribed by physicians for FRDA patients and covered by medical insurance. The plan in this trial is to administer Idebenone at a high enough dose to explore benefit not only in the cardiac symptoms but in neurological symptoms as well. Also in this trial, patients will be observed in hopes of determining if the changes observed in the heart in cardiac wall thickness, for example are actually beneficial to the patient. The basic question in that regard is, "Are such changes accompanied by indications of improved heart function." Phase I of this Idebenone trial was conducted at the NIH with the purpose of establishing the maximum tolerated dose of Idebenone and selecting the dose to be administered in subsequent phases. In addition to the primary, stated objectives of the trial, we recognize that there will be substantial benefits that go well beyond them. The trial will focus the attention of many of our finest FRDA scientists who will undoubtedly learn a great deal about this disorder, gaining insights that will likely propel them to additional breakthroughs. Also, because this will be a multi-center trial, it is greatly increasing and refining the collaboration of FRDA scientists across institutional boundaries. Finally, in preparing for this trial, we are establishing for the first time, and then exercising, the clinical-trial-conducting mechanism that will serve the FRDA community well in all subsequent trials. With a lot of momentum behind it, FRDA has entered the all-important clinical trial phase a phase that will not end until we have definitive treatments or a cure. Idebenone is not the only antioxidant in clinical trial. In a four-year pilot study in London, one team of researchers led by Dr. Anthony Schapira and Dr. Mark Cooper has administered CoQ10 and Vitamin E and monitored impact on heart, skeletal muscle, and ataxia scales. The preliminary results of the study indicated a substantial increase in energy metabolism in both cardiac and skeletal muscle. There was no worsening among these patients in ataxia scale scores or cardiac hypertrophy. Cardiac fractional shortening increased significantly. Mitoquinone: Currently in development and impressively briefed at the 2003 conference is MitoQ (mitoquinone). The New Zealand scientists developing MitoQ are attempting to target antioxidants specifically to the mitochondria, which is where FRDA's oxidative stress originates. These scientists, led by Dr. Michael Murphy, Dr. Robin Smith, and Dr. Ken Taylor, are trying to concentrate the antioxidant in this case a quinone very similar to CoQ10 in the mitochondria by attaching it to an element whose electrical charge pulls it through the membranes of the mitochondria. Early experiments in healthy mice seem to indicate that the technique is effective in getting the antioxidant to mitochondria in the heart, skeletal muscle, liver, and brain. The MitoQ effort includes, under a FARA grant, testing the compound in cell cultures and FRDA mouse models in England and France with hopes of trying it in human subjects at a later date. The same scientists are exploring additional antioxidants targeted to the mitochondria in the same way. For example, they are investigating the effectiveness of directing Vitamin E to the mitochondria in a form they call MitoVit E. It was evident at the 2003 conference that this new approach of targeting antioxidants to the mitochondria is very promising and we are eager to see the results as the project moves through animal studies and then to human trials. jump to top Ataxia Scales (Clinical Measures)
Treatments will not be developed without clinical trials and clinical trials will not be successful without clinical measures. Without such clinical measures to demonstrate that a drug has beneficial effect on patients, the Food and Drug Administration (FDA) will not approve the drug, doctors will not be able to prescribe it for FRDA, and it will not be covered by U.S. health insurance plans. The current, multi-center study designed to put the required ataxia scales in final form is being led by Dr. David Lynch of the Children's Hospital of Philadelphia and University of Pennsylvania and also involves six other centers around the United States Emory University, UCLA, and the Universities of Iowa, Minnesota, Mississippi, and Texas. In addition to Dr. Lynch in Philadelphia, the study's Investigators are Dr. George (Chip) Wilmot (Emory); Dr. Susan Perlman (UCLA); Dr. Henry Paulson (U. of Iowa); Dr. Christopher Gomez (U. of Minnesota); Dr. S.H. (Sub) Subramony (U. of Mississippi); and Dr.Tetsuo (Tee) Ashizawa (U. of Texas). FARA and MDA are cooperating to fund this multi-center study. FARA also funded the research Dr. Lynch conducted to build the preliminary data and structure of the study, as well as the two previous sessions at the National Institutes of Health (NIH) designed to test previously available ataxia scales for potential application to FRDA trials. The current study does not involve the administration of any drugs and will not require participants to alter their current practices regarding drugs and medications they might already be taking. The clinical measures to be tested and refined in this study include the 9-hole pegboard test, a quantitative speech measure, a timed 25-foot walk (when possible), a quantitative visual function measure, and quality of life measures. The preliminary research funded to date by FARA and MDA has demonstrated that these measures do correlate with markers of disease severity. The multi-center study will determine the extent to which the measures are sensitive to changes resulting from disease progression and the drugs to be tested in clinical trials. This large, multi-center effort and future clinical trials would be far more difficult, time-consuming and error-prone if researchers relied on hand-written data entries. The FARA volunteers (see articles on p. 9 of 2004-2005 FARA Update and p. 9 of 2003-2004 FARA Update) will insure that this study and subsequent FRDA clinical trials are "paperless trials" in which data is electronically entered, verified, transmitted, and collated, and in which patient registries and databases are generated, secured, maintained, and mined. FRDA clinical trials will not be successful without the clinical measures to be developed in this study. This study will be successful only with patient participation. Treatments and a cure will be developed only if FRDA patients enroll and participate in this study. Please see the information on Patient Recruitment and contact the center nearest you to enroll as soon as possible. The sooner this study is completed, the sooner FRDA clinical trials can be successful. jump to top Gene-based Approaches
FRDA's lengthy tri-nucleotide (GAA) repeats appear to cause one side of the double helix to fold back onto itself and form the bonds of a tangled structure being called a triplex or "sticky DNA." This tangle greatly diminishes the molecular transcriber's ability to get past the repeated sequences to read the genetic code on the FRDA gene. Normally, the molecular transcriber (RNA polymerase) slides along the DNA and makes a copy of the genetic code and passes that code to the messenger RNA. The messenger RNA then moves into the cytoplasm outside the cell nucleus and collects the amino acids called for, and in the order dictated, by the genetic code. In the FRDA patients' cells, the molecular transcriber seems to have a hard time sliding past the tangle and reading the FRDA gene's code, so it often stops and moves on to the next gene. In those cases, the FRDA gene's code is not read and passed on to the messenger RNA and the Frataxin protein is not formed, thus causing the disorder. The code for each gene is not laid out uniformly along the length of the gene. Rather, it is found in segments of the gene called exons. Between these exons are segments of nucleotides, called introns, of no apparent value. One hopeful aspect of the FRDA gene's "sticky DNA" is that the GAA repeats are found in an intron (the first intron) in the FRDA gene. The fact that the "sticky DNA" is contained within the "junk mail" of an intron rather than on an exon with important genetic code, gives rise to additional hope that a procedure can be developed to destabilize, cut or contract the tangle so that the molecular transcriber can get past the "sticky DNA" and move on to read the genetic code on the exons. FRDA scientists are intently exploring prospective gene-based repair mechanisms. Their various research projects include a wide range of promising approaches. One such approach involves what Dr. Robert Wells has referred to as molecular surgery an attempt to design and deliver a molecule that would sever the triplet-repeat expansion from the FRDA gene. If the triplet-repeat expansion were removed from the gene, the gene's code could be transcribed more readily and more frataxin protein could be produced. Another approach is to attempt to attach to the triplet-repeat expansion region of the FRDA gene additional pieces of DNA (oligonucleotides) that would interrupt or stabilize the expansion. If the expansion could be interrupted or stabilized effectively, it might not "supercoil" and tangle into the "sticky DNA" that makes it difficult for the gene's code to be transcribed and the frataxin protein to be produced. Dr. Chris Everett and other scientists working at the National Institute of Neurology in London believe they have evidence indicating that the triplet-repeat expansions might have some negative impact on chromatin the substance in which DNA is packaged in the chromosome and that the consequent changes in chromatin might be responsible for the FRDA gene expressing less frataxin protein. If so, a different therapeutic avenue would open, in that scientists could identify agents able to reverse the changes in chromatin. Another approach is based on the knowledge that the FRDA triplet-repeat expansions are naturally unstable between generations and differ among cell types. FRDA scientists, for example, estimate that fathers, 90 percent of the time, pass along to their offspring shorter FRDA triplet-repeat expansions than they have themselves, while mothers pass along shorter expansions at about the same rate as they pass along longer expansions. FRDA scientists also know that FRDA expansion lengths are unstable in somatic (non-reproductive) cell division, leading to some variation in repeat lengths among cells a phenomenon referred to as mosaicism. The more FRDA scientists can learn about such generational and cellular differences and the factors that cause them, the more likely it is that they will be able to manipulate or replicate such differences so as to encourage or force reductions in expansions and consequent reductions in the severity of FRDA symptoms. According to Dr. Massimo Pandolfo, a member of FARA's Board of Directors and its Scientific Review Committee, a direct correlation has been established between the size of the GAA repeat lengths (especially the smaller of the two) and earlier age of onset, earlier need for a wheelchair, more rapid rate of disease progression, and presence of "non-obligatory" disease manifestations (e.g., cardiomyopathy, diabetes). However, Dr. Pandolfo adds that differences in repeat lengths account for only about half of the variations in age of onset, indicating that other factors, such as mosaicism modifying genes and the environment, could possibly influence disease progression. A number of FRDA scientists are attempting to decipher some of those modifying factors in hopes of establishing the basis of a therapeutic avenue. Knowing, for example, that Acadian (Cajun) FRDA patients apparently have somewhat later onset and milder symptoms than would be anticipated from their expansion lengths, some FRDA scientists have undertaken to identify the differences between Cajun and non-Cajun FRDA genes. They hope to determine what differences in the Cajun genes result in milder symptoms so as to explore how such differences could be replicated in a therapeutic approach. Dr. Bronya Keats of Louisiana State University, a member of FARA's Board of Directors and Acting Chairperson of its Scientific Review Committee, has been a leader in this effort. Dr. Grabczyk and Dr. Wells have also made valuable contributions in this area, and Dr. Karen Usdin at NIH is pursuing a project in this area as well. Dr. Michael Brown, a geneticist specializing in mitochondria at Mercer University, received a FARA grant to investigate another possible explanation of these FRDA variations. Mitochondria have their own DNA and Dr. Brown is studying samples from FRDA patients to test his hypothesis that mitochondrial DNA might have a modifying impact on FRDA phenotypes (symptoms). He is studying Cajun-patient samples being provided by Dr. Keats, and non-Acadian patients being provided by Dr. David Lynch at the University of Pennsylvania and Dr. "Chip" Wilmot at Emory University. Another gene-based approach is being explored in Duchenne Muscular Dystrophy by a team in Australia led by Dr. Robert Kapsa. Dr. Kapsa's approach involves introducing to the appropriate portion of the disease gene a small amount of DNA that would serve to bypass or "patch over" the genetic defect. The approach was developed for Duchenne Muscular Dystrophy which, like the vast majority of diseases, is a point-mutation disorder, but Dr. Kapsa reports that he believes that, if the technique could be developed effectively, it could be applied to FRDA point mutations as well as the triplet-repeat expansions. In a point mutation, the attempt would be to replace the incorrect or missing nucleotide, whereas for triplet-repeat expansions, the attempt would be to "patch over" the expansions. An additional potential gene-based approach is referred to as gene replacement therapy, in which the entire FRDA gene would be replaced by an unaffected gene. In still another approach, researchers are beginning to explore pharmacological approaches to addressing the FRDA genetic defects. In these pharmacological approaches, scientists are seeking drugs molecules that "upregulate" the gene's expression of the frataxin protein. In that regard, FARA has awarded grants to excellent scientists at the Scripps Research Institute in La Jolla, California (Dr. Joel Gottesfeld) and the California Institute of Technology in Pasadena, California (Dr. Peter Dervan), as well as to their collaborators at Texas A&M (Dr. Robert Wells) and at the Erasmus Hospital in Brussels (Dr. Massimo Pandolfo). This superb team's findings thus far are extremely encouraging, showing the possibility that a particular molecule, designed by Drs. Dervan and Gottesfeld, may be effective in significantly increasing production of the frataxin protein in FRDA patients. Many of the potential gene-based therapies would require a delivery vehicle, usually called a vector, that would take the therapeutic mechanism or material to the right parts of all the right cells in the body. FARA is supporting a team in Australia, led by FARA grant recipients Dr. Ian Alexander and Dr. Jane Fleming, that is making excellent progress in developing such vectors for FRDA. Drs. Alexander and Fleming told the 2003 conference participants that they are testing virus vectors in delivering FRDA genes to human and mouse model cell cultures and will soon attempt delivery "in vivo" into a living mouse model very important work being funded by FARA grants. jump to top Protein-based Approaches
FRDA scientists know much about the frataxin protein. They know that when the FRDA gene is transcribed correctly, the gene's code results in the assembly of 210 amino acids in a particular order and that these amino acids "fold elegantly" into the frataxin protein that moves to perform its function at the walls of the cell's mitochondria. They know, too, that the frataxin protein plays an important role with iron. The key unanswered question concerns the protein's precise function with iron. Does the protein escort (or "chaperone") iron, maintaining the iron in its benign, plus 2 state (Fe+2), so that the iron does not oxidize (give up an electron), transition to Fe+3 and contribute to the production of the free radicals that damage cells? Or, does the frataxin protein not only maintain the iron in its benign state but actually participate along with other proteins in the assembly of the iron-sulfur clusters important in the mitochondria's production of energy? The scientists who presented their insights at the 2003 conference are leading the way in determining the answer. In the meantime, other scientists are launching their own attempts, even before the protein function issue is resolved, to make progress toward a protein-based FRDA therapy. For example, FARA awarded a grant aimed in that direction to a Wake Forest University (WFU) team led by Dr. Mark Payne. The WFU team's extensive work on cancer and heart disease included research on proteins that are expressed in the cell's nucleus but function in the cell's mitochondria. The team developed a technique for synthesizing such proteins when they are in short supply and then delivering them to mitochondria. The delivery device was a fusion protein that can be attached to the target protein, escort it across the blood-brain barrier into the cell and directly into the cell's mitochondria, where the target protein is left to perform its function. Knowing that the frataxin protein is expressed in the cell's nucleus, functions in mitochondria, and is in short supply in FRDA patients, the WFU team aims to synthesize frataxin and deliver it to mitochondria, first in cell cultures and then in FRDA mice. FARA is assisting the WFU team by funding this research and in obtaining FRDA mice for the project. jump to top Animal Models
Much of what scientists know about the basic, underlying mechanisms involved in Friedreich's ataxia they have learned from investigating very similar genetic structures in non-human models. While much of the early work in this regard made use of yeast, FRDA scientists are now working hard to refine a far more useful model for investigating the disorder a mouse model. With a viable mouse model that comes close to replicating the human disorder, scientists will be better able to determine more precisely exactly how the disorder develops and how and where it does its damage. They will also be able to test various potential therapies and gauge their impact at different stages of development, even in pre-symptomatic stages of the disorder in the mice. A variety of approaches have been taken to developing FRDA mouse models. One has been the "knock-out" mouse. Scientists can disrupt or delete the FRDA gene on one or both alleles of a mouse. "Knocking out" one gene produces an asymptomatic mouse similar to a carrier. Unfortunately, "knocking out" both genes leaves the mouse with no Frataxin protein at all, and the mouse dies in the embryonic stage, showing that life cannot be sustained in the total absence of the Frataxin protein. In order to generate a mouse model that is viable and has a disease closely resembling FRDA in a human, scientists are attempting to reduce significantly the amount of Frataxin the mouse produces while leaving a sufficient amount to sustain life and approximate human symptoms. Consequently, other approaches are being taken, such as developing "knock in" mice in which the healthy Frataxin genes are replaced on both alleles with a mutant gene with GAA expansions. A third approach has been to cross "knock-out" mice with "knock-in" mice in hopes of developing mice that approximate the human disorder and symptoms and that live long enough to be useful in lab experiments. FRDA scientists have now developed a number of FRDA mouse models. A French team led by Helene Puccio and Michel Koenig, for example, now have several different strains of "conditional knockout" mice, one of which seems to approximate the human FRDA cardiac symptoms while the other seems to approximate the human FRDA neurological symptoms. Other scientists, like Dr. Mark Pook, Dr. Massimo Pandolfo, and the lab of Dr. Panos Ioannou are developing mouse models that carry GAA expansions, hoping that the mice will develop symptoms that more closely approximate a full range of the human FRDA symptoms. jump to top Iron Chelation
One of the most important results of the identification of the FRDA gene was that it permitted scientists to identify the protein encoded by that gene and then to investigate the function of that protein. The evidence has been steadily mounting on the function of the Frataxin protein. It appears that Frataxin, once it is formed in the cell's cytoplasm by the messenger RNA's collection of amino acids, moves to the mitochondria of the cell where it is involved in the import, export, and metabolism of iron at and within the mitochondrial walls. If insufficient Frataxin is available, as is the case in FRDA patients, excessive iron apparently builds up in the mitochondria. The reaction of the iron with oxygen then appears to produce toxic free radicals that damage and kill the cell. Preliminary evidence indicates that a sufficient amount of Frataxin serves to bind up, store, escort, and facilitate proper use of the iron in a way that prevents it from building to excessive levels and reacting with oxygen to form damaging free radicals. A number of scientists, primarily Dr. Des Richardson and the lab of Dr. Panos Ioannou in Australia, are attempting to develop a compound and a process with which iron could be removed from the mitochondria that lack sufficient Frataxin to govern iron levels and reactions. Such a process is called iron chelation. One of the chief challenges in this work is to identify a chelating compound that would reduce the level of available iron in the mitochondria while not altering the balance of iron elsewhere in the cell to a harmful extent. This important work continues at several centers and FARA is engaged in supporting it. This work in iron chelation, like so many other avenues of FRDA research will benefit greatly from the development of FRDA animal models. jump to top The Promising Road Ahead
In the international FRDA research community, many shoulders are being put to the wheel to push us together across the finish line. It is no surprise to hear from FRDA scientists, as we do, that they are excited and confident. They also report that, within the scientific community, Friedreich's ataxia is "a hot field" that is drawing more and more scientists into this research. FARA is receiving research grant applications that are growing rapidly in number and promise. FARA continues to be committed to working together with the NIH and other grant-making organizations to support the current FRDA research community and to help "grow the field" by encouraging additional scientists to invest their talents in the search for treatments. FARA continues to need your help acting alone, there is little any of us can accomplish, whereas acting together, there is little we can NOT accomplish. jump to top FARA's Mission and Vision for Rapid Progress
FARA's mission is to support scientific research leading to treatments and a cure for Friedreich's Ataxia (FRDA). We will accomplish that mission by identifying and supporting the research that will slow, stop, and reverse the damage caused by this disorder. FARA is fortunate to be funding and otherwise facilitating research that shows tremendous potential in all three of those mission areas. The foundation for progress in all three mission areas, of course, is laid by the advances we are enjoying in basic science. We are deeply indebted to the scientists that have identified the FRDA gene, deciphered its mutations, analyzed the composition and function of its protein, and sorted out the mechanism of the damage being done. None of the progress being made in slowing, stopping or reversing this disease would be possible without the marvelous advances in such basic understanding. More needs to be done in this basic science arena but, based on the giant steps taken to date, promising research is underway in all three mission areas. For the most part, the research being conducted on antioxidant therapies (Idebenone, CoQ10, MitoQ, etc.) we can consider in the first mission area-slowing the disease progression and providing our scientists and our patients more time to make advances in the other two mission areas. We are supporting a wide spectrum of research aimed at stopping the disease. The common ground shared in most of these investigations is the attempt to increase the availability of the frataxin protein. Some scientists are pursuing that goal with gene-based approaches to delete, repair, or stabilize the mutation so that more of the protein is produced. Others are working to synthesize the protein and deliver it to the mitochondria directly. In whatever way it is accomplished, making more of the frataxin protein available in the right place holds the promise of stopping the disease in its tracks. In both of these first two mission areas, we support a variety of promising approaches and monitor progress closely, looking for the optimum approach or combination of approaches that will take us to treatments. The third mission reversing the damage, regenerating lost capabilities seems to present considerable challenges. We do anticipate that a small amount of reversal will be achieved when we are able to slow and stop the disease, because some "sick" cells will be rescued in the process. However, scientists do not yet know how to rescue the cells that are already dead, so more significant reversal will await a different approach. Currently, the approach that seems most promising in that regard is stem-cell research. FARA will leave no stone unturned in its commitment to accomplish all three missions. Much progress has been made and continues to be made in the projects we are all supporting around the world. Especially in slowing the disease, antioxidants and other drugs are moving from drug screening to animal models and the large human trials needed to obtain approved therapies. We need to continue accelerating that process by working closely with the NIH, the other scientists preparing the drug screenings, animal experiments and clinical trials, and with the pharmaceutical companies interested in supporting clinical trials and developing additional drugs. As that "slowing" process advances, we need to take the "stopping" and "reversing" research to the next level. To go to the next level in the gene therapy and protein therapy, for example, needed to stop the disease and the stem-cell research needed to reverse it, our strategy is to get excellent scientists, who develop such therapeutic technologies and approaches for a living, together with our excellent scientists who know enough about FRDA to determine how to apply those technologies and approaches to FRDA. We need to continue to encourage the best minds to think about FRDA and to do research on FRDA, because no single scientist or group of scientists has a monopoly on good ideas and no single group of scientists can "do it all." We have therefore begun establishing fruitful collaborations with key institutions accomplished in the types of scientific endeavor needed to stop and reverse FRDA. For example, FARA has awarded grants to excellent scientists at the Scripps Research Institute in La Jolla, California (Dr. Joel Gottesfeld) and the California Institute of Technology in Pasadena, California (Dr. Peter Dervan), as well as to their collaborators at Texas A&M (Dr. Robert Wells) and at the Erasmus Hospital in Brussels (Dr. Massimo Pandolfo), and this superb team's preliminary results show tremendous promise. FARA is also exploring, with the Burnham Institute in La Jolla, which helped lead the California consortium instrumental in passage of the California referendum on embryonic-stem-cell research, the prospects for investigating stem cells in the context of reversing the damage of Friedreich's ataxia. FARA will continue to collaborate with such accomplished institutions capable of helping accomplish our mission. Another key area of collaboration is with elements of the pharmaceutical community. As FRDA scientists continue their promising progress toward therapeutic discovery, we need to put in place the support structure we will need to take such discoveries through subsequent steps. For example, when our scientists discover a drug that is beneficial, we need to accelerate the drug through pre-clinical research and clinical trials, drug development and make it available to patients. FARA has helped make giant strides in establishing the required clinical structure. NIH has conducted Phase I of the Idebenone trial and is prepared to play a leading role in subsequent phases. FARA is working closely with the pharmaceutical companies involved in developing and producing Idebenone. FARA is also supporting the seven centers across the United States that are refining the ataxia scales required for measuring therapeutic effect in FRDA clinical trials. FARA is also consulting with experienced experts in drug discovery, drug development, clinical trials, and drug marketing to ensure that the appropriate mechanisms are in place to take beneficial therapies to patients when the time comes.
This comprehensive research strategy is ambitious, but we need to be ambitious to slow, stop, and reverse this disease. With your continued, generous support, this strategy will be successful. FRDA scientists are increasingly certain they will conquer Friedreich's ataxia. They are convinced it is no longer a question of "if" but, rather, a question of "when." They tell us, too, that what we have all done together already has taken years off the road to "when." We need to continue to build our momentum and drive this research across the finish line of treatments and a cure. |
