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Testimony Before the Senate Subcommittee on Labor, Health and Human Services, and Education Committe on Appropriations September 28, 1999 Testimony J. William Langston, M.D., President The Parkinson's Institute Good morning. It is a pleasure and honor to be here. I would like to begin by briefly describing my own background. I am a neurologist, and have dedicated my entire professional career to research and patient care in Parkinson's disease. I have published 250 papers in the area and I see patients with this disease every day. I am also founder and President of the Parkinson's Institute in Sunnyvale California, located in the heart of the Silicon Valley. My goal today is to impart the sense of excitement, promise, and urgency that currently pervades the Parkinson's disease research community. I believe with adequate resources and manpower, we can solve the complex riddle of Parkinson's disease. Research opportunities abound - never before have we had so many new leads. But we must pursue these leads as vigorously as possible if we are to conquer this terrible disorder. I would like to begin with research on the cause. As a result of a study published earlier this year in the Journal of the American Medical Association, we now have a much clearer picture of how to invest our resources to achieve this. This NIH funded study involved interviewing all of the living twins who served in World War II. Nearly 20,000 twins were interviewed, the largest twin study ever done for Parkinson's disease. After examining all of the identical and fraternal twins with suspected disease, the results showed that typical Parkinson's disease, when beginning over the age of 50 is not due to genetic causes, but rather must be caused or triggered by something in the environment. For the research community, this is a huge branch point. It means that we can and should focus on environmental influences by studying populations of individuals, including the WW II twins. Such studies require major investments of time and money, but with this new data we now know that such an investment is worth it. Studies to date have pointed to pesticides, herbicides, rural living, certain heavy metals, and of course there is the inverse relationship to cigarette smoking. Let me stress that, if causative agents can be identified in the environment, ways to avoid and/or minimize effects of exposure could lead to primary prevention of the disease. This is our ultimate dream. Does this mean there is no role for genetics? Not at all. Unexpectedly, the same study in twins showed that when parkinsonism begins earlier in life there is a strong genetic component. I think I can safely state that there is a near unanimous consensus in the research community that unraveling the genetic parkinsonisms, while solving a very small percentage of the cases, will provide invaluable new clues on the cause of typical Parkinson's disease. Finding new mutations that cause parkinsonism will lead to identification of new genes. This will lead to the identification of new proteins that may be key players in the process of cell death. Let me give an example. In 1997, investigators at the Human Genome Project identified a mutation in a form of familial parkinsonism. The mutant gene produces a protein known as (-synuclein. It turns out that only a few families on earth have this mutation, but this same protein has been found to aggregate in nerve cells in virtually all cases of typical sporadic Parkinson's disease, in structures know as Lewy bodies. This has opened up an entirely new avenue of research, and raised the possibility for the first time that Parkinson's disease may be a protein aggregation disorder, something that has been suspected for years in Alzheimer's disease. A second and entirely different mutation has already been identified in another form of familial parkinsonism, and I suspect there will be many more. The affected proteins can be used to model Parkinson's disease in transgenic mice, and can be used to study mechanisms of cell death. An all out approach to identify new genetic forms of parkinsonism could have scientific yield, and we are just in the beginning stages of this research. And this is only one of the many areas of laboratory investigation that are currently underway to better understand Parkinson's disease. Areas currently under investigation include studies on free radicals, excitotoxicity, nitric oxide, the process of programmed cell death, and even inflammation as possible causes of cell death in Parkinson's disease. Each represents an exciting and important area of basic research, which, if positive could have enormous therapeutic repercussions. If we can identify the mechanisms by which these cells are dying in the brain, even if we don't know what kicks the process off, we may be able to intervene by blocking the process, and slowing or halting disease progression. This could lead to secondary prevention if we could identify the disease in its pre-clinical state, something I will return to later. Now I would like to turn to patients who have already affected and disabled to a greater or lesser degree by Parkinson's disease. Primary and secondary prevention are exciting goals, but what can do for those who have already been damaged by the disease? We must find ways to repair or restore the damaged areas of the brain. It sounds impossible, but in fact new strategies are emerging constantly. To explain how this works, I need to give you a brief primer. In Parkinson's disease, the brain cells that make a substance called dopamine begin to die. Without dopamine, the motor system shuts down, leaving patients frozen and unable to move. Because the brain is incapable of making new cells, one of the few hopes for a cure is what we call cell replacement therapy. Progress in neural transplantation has been substantial over the last 15 years. We now know that this technique is feasible and safe. Furthermore, it is known that transplanted cells survive after transplantation into the brain and are capable of exerting therapeutic benefit, although technological barriers remain (for example, only approximately 10% of cells survive). However, in recognition that the use of human fetal tissue is likely to be limited in the foreseeable future, an intensive effort is under way to find alternatives. Promising lines of research in the use of xenografts, bioengineered cell lines, and the used of progenitor or pluripotent cells. The latter are in the earliest stage of development, but may be the most exciting in the long term. Any success in this area could lay the groundwork for serious attempts to cure this disease. To quote my colleague, Dr. Fred Gage, Ph.D., of the Salk Institute, a preeminent researcher in this area, "This is an ambitious agenda which, while focusing on Parkinson's disease, if funded in excellent laboratories, will yield broadly relevant results." How do we best get there, the most quickly? To quote Dr. Gage again, "One should consider establishing regional testing centers, where reliable models in rat, mouse and monkey are routinely established; where basic investigators can apply to try out their latest ideas without having to set up the models in their own labs and learn by making all the mistakes that have already been made. These centers could also be places where better models are being designed all the time. These centers could eventually form an alliance with clinical trials to make sure that the trial reflects what is really known from the pre-clinical work, and if a clinical trial is conducted, it would be done in such a way that no matter how it turned out, the pre-clinical centers could take the results and build on them." There is an alternative strategy that should be vigorously pursued. This involves reviving or restoring cells that are still in the brain, but are non-functional. Even though most of dopamine is gone, only about 60 % of cells are lost, well below the threshold that leads to symptoms. This means that there are many cells still present that are not functioning. If we can turn on even half of these remaining brain cells, we might be able to reverse the parkinsonism entirely, and there are substances that may do this. Growth factors are being actively investigated, but do not get into the brain. A new family of trophic factors called neuroimmunophilins has been discovered in the last few years. These compounds can cross the blood-brain barrier, and if effective, could accomplish everything we hope to achieve with surgery, without the surgery. This brings me to currently available surgical techniques. The last decade has lead to a true renaissance in surgical approaches for Parkinson's disease. This was the direct result of the powerful model for Parkinson's disease, which has allowed us to learn great deal about the circuitry of the basal ganglia. For the first time we know where to intervene to balance out the abnormal brain circuits in Parkinson's disease. A particularly exciting innovation is the use of deep brain stimulation. Electrodes are placed deep in the brain, and stimulated using a device that resembles a cardiac pacemaker. This technique is as effective as older ablative procedures, but not permanent and therefore much safer. It can be done on both sides and in areas of brain that we could not otherwise approach. One deep stimulation area in particular has been found to be very effective, the subthalamic nucleus or STN. Indications are that between ten to thirty per cent of patients may be able to go entirely off medications. But to continue this work, a great deal of work needs to be done, both experimentally and in practice. We still don't understand how it works and we may not have found the best area to stimulate yet. Few centers in the country are trained or experienced to do this type of surgery, and because of expense, large scale trials have yet to be done. A great deal of work lies ahead of this to bring this exciting new technique to fruition. Finally, I want to draw your attention to a critical research area where there is a huge gap, and that is the need for a biomarker. Simply put, this is a biologic test that can be used to determine presence or absence of a specific disease. At the moment there is no biomarker for Parkinson's disease. We desperately need one because clinical examination is accurate only about 75% of the time. This means we are wrong 1 out of every 4 times. This not only affects patient care, it can severely affect research. For example, when investigating the cause, if some of the patients you are studying don't even have the disease you think they do, one might easily miss a vital clue as to the cause. In carrying out new drug trials, mixing in misdiagnosed patients could dilute out an otherwise positive result. Fortunately we have an exciting start in this area with new imaging procedures. Positron imaging technology is a powerful way to look at the brain during life, but for cost and technical reasons will likely remain a research tool. A newer technology, called SPECT scanning, could be widely used, but at the moment less than a handful of centers are doing this procedure, and we have a long way to go before this can be widely used for both research and practice. The other major gap is that there is much more to be learned from it. In the long run, we will really need a biomarker that can be used to screen the general population for pre-clinical disease. If that can be developed, and we could learn more about the mechanism by which cells die, we may be able to intervene to halt the disease with "neuroprotective agents" before it even appears clinically, something that could be the near equivalent of cure. In summary, I would like to close by saying that I believe that this could be a historical day for Parkinson's disease research. I hope that, by the end of this hearing, we will have convinced you that a major research investment is not only critically needed, but fully warranted. I truly believe that we are at a place in the scientific history of research on Parkinson's disease where such an investment could yield huge scientific dividends. If so, our society and the patients we serve will be the real winners. Thank you for you kind attention. <http://www.parkinsonsaction.org/press3.html> janet paterson 52 now / 41 dx / 37 onset 613 256 8340 po box 171 almonte ontario canada K0A 1A0 a new voice: <http://www.geocities.com/SoHo/Village/6263/> <[log in to unmask]>