A wave of new drugs and therapeutic interventions for Parkinson’s disease has dramatically changed the research landscape in the past decade. As we move forward in the 21st century, further advances in pharmacotherapy and neurosurgery will likely lead to even more effective treatments. Does this progress mean that the scientific community is close to finding the cause of, and perhaps even a cure for, Parkinson’s disease?

“I think there’s a good chance we are going to find the cause before we find the cure,” said J. William Langston, MD, in an interview with NEUROLOGY REVIEWS. “There’s so much evidence out there, and it ranges from laboratory evidence to many clues from epidemiologic studies…. I think there are enough pieces to the puzzle that with the right support, funding, and studies, it’s quite conceivable to me that we could find the cause of this disease in the not too distant future. On the treatment side, it’s tougher.” Dr. Langston is Scientific Director and Chief Executive Officer of the Parkinson’s Institute in Sunnyvale, California, and Chief Scientific Advisor to the Michael J. Fox Foundation for Parkinson’s Research.

“If we could find one or more drugs that would halt progression, then I think there’s a chance that we could pretty much eradicate this disease as a disabling disease,” Dr. Langston continued. “One of our goals is to search very intensively for new agents that might slow or halt progression, and, honestly, I think that’s more likely to occur than finding a cure.”

Meanwhile, Jeff Bronstein, MD, PhD, believes that certain issues need to be addressed before there is a chance of preventing Parkinson’s disease. “I think it is realistic to identify risk factors and people who are at risk in much the same way as we do in vascular disease,” Dr. Bronstein told NEUROLOGY REVIEWS. “We will be able to delay the onset or prevent it in many people. There is no one big key. Genetics and epidemiology will identify targets that need to be tested in the laboratory.” Dr. Bronstein is Director of the University of California, Los Angeles, Movement Disorders Program.

HISTORY AND RECENT BREAKTHROUGHS

Parkinson’s disease is the second most prevalent neurodegenerative disorder, affecting about 50,000 Americans each year, with more than half a million having the disease at any one time. It strikes men and women alike and has no social, economic, or geographic boundaries. British physician James Parkinson first described the disorder as “the shaking palsy” in 1817. One of the most significant breakthroughs occurred in the early 1960s, when researchers identified a fundamental brain defect that is a distinguishing characteristic of the disease—the loss of brain cells that produce dopamine, which helps direct muscle activity. This discovery led to the first successful treatment for Parkinson’s disease and enabled researchers to devise new and better therapies.

Among the more recent advances, the three that have had the biggest impact have been in genetics, mitochondrial defects, and functional imaging of the dopaminergic system, Dr. Bronstein said. Dr. Langston offered that the discovery of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and work that has been done since then in looking at environmental factors has signified a major change in the direction of the field. “The discovery of rare genetic forms—while I don’t think that changes my feeling that the disease is genetic; I think it’s not—has been tremendously informative in terms of basic science and in helping us try to understand why cells die in Parkinson’s disease,” said Dr. Langston. “Deep brain stimulation is providing benefits in cases of late-stage disease where previously there was no alternative. Deep brain stimulation also came out of the MPTP model, because that’s where they discovered that the subthalamic nucleus was very overactive in the disease, and the concept was to, using these electrodes, somehow inactivate that nucleus.”

GENETICS VERSUS ENVIRONMENT

The genetics versus environment debate pertaining to the possible origin of Parkinson’s disease began about a century ago and it continues today. Some investigators are looking at possible environmental factors, such as toxins that may trigger the disorder, while others are studying genetic factors to determine how gene mutations play a role.

“There is no doubt that both are important,” said Dr. Bronstein. “People argue over the relative importance of each, but I think both sides are correct in given individuals. For example, someone with a parkin mutation is heavily weighted toward a genetic etiology, although the environment clearly influences when and how bad some of the phenotypes will be. Other individuals are likely to have high exposure to environmental toxins, such as pesticides, without a strong genetic predisposition, which leads to the disease. I do feel that young patients with Parkinson’s disease in general likely are more influenced by genetics, and older individuals less so.”

“I think in the last two or three decades we’ve seen huge progress on both fronts,” said Dr. Langston. Does that mean genetics is important in relation to Parkinson’s disease after all? “The answer is yes and no,” Dr. Langston answered. “I personally believe, based on the twin study [by Caroline M. Tanner, MD, PhD, and colleagues] that we did at the Parkinson’s Institute, that genetics is not a primary determinant of Parkinson’s disease. Our twin study suggested strongly that the typical disease occurring over the age of 50, which is 97% of all cases, does not have a primarily genetic origin. But there are two reasons that I think genetics are really important. First, these very rare genetic cases can sometimes give you tremendous research leads…. Second, I still think it’s a possibility—though I’m not sure how strong it is—that while genetics is not the key factor, it certainly may be a predisposing factor. There may be genetically inherited risk factors…. There’s an old saying that ‘genetics loads the gun, but environment pulls the trigger.’ So it could be that genetics is important in deciding who is at risk.”

In an effort to encourage collaboration in the study of genetics relating to Parkinson’s disease, the Michael J. Fox Foundation for Parkinson’s Research recently announced funding for a new initiative, the Global Genetics Consortia. “There is a huge amount of data out there from many different centers,” said Dr. Langston. “There’s not enough cases to really reach any type of definitive conclusion. So the concept is to encourage investigators to pull together all of the labs that are, say, working on one particular mutation. The data are already collected. [The goal is] to really try to definitively establish whether some of these chromosomal associations are real, how common they are, and perhaps even work toward discovering some new mutations that lead to Parkinson’s disease.”

PARKINSON’S DISEASE RESEARCH AGENDA

“Slowing disease progression is the most important issue,” said Dr. Bronstein. “It will likely require more information on the pathogenesis of cell loss. This will likely include genes that cause Parkinson’s disease and make people vulnerable to environmental insults. I believe there will be several factors that will differ in individuals, so it will be important to identify those factors for each person. This is similar to vascular disease. Some people require antihypertensive agents, while others require cholesterol-lowering agents.” Another noteworthy goal, added Dr. Bronstein, is developing therapies for nondopaminergic symptoms (nondopa-responsive symptoms).

In addition, since it was discovered that MPTP causes parkinsonian symptoms in humans, researchers have found that by injecting MPTP into laboratory animals, they can reproduce the brain lesions that cause these symptoms. Others are also investigating the role of mitochondria in Parkinson’s disease. Because MPTP interferes with the function of mitochondria within nerve cells, some believe that similar abnormalities may be involved in Parkinson’s disease. Another key area under investigation is dopamine transporters, which carry dopamine in and out of the synapses.

GROWTH FACTORS

One particularly promising area of research is the use of growth or trophic factors to treat Parkinson’s disease—in particular, glial cell line–derived neurotrophic factor (GDNF), offered Dr. Langston. In one recent study, he said, “they did something that I would call ‘down and dirty.’ They just put a cannula in and infused GDNF right into the key area of the brain—the striatum. And in an open-label trial, most of those patients really did better.… Intuitively, it’s an attractive way to go, and we have at least open-label preliminary evidence that this could be really helpful in Parkinson’s disease. The caveat is that if you go back and look at the original open-label human trials with fetal cells, the results were so impressive that you just couldn’t believe that it wasn’t going to work. The initial results were so dramatic; it took a large controlled trial to find out the treatment didn’t really work. So I think one has to be very cautious in putting too much weight on an open-label trial.”

For a person to develop Parkinson’s disease, he or she has to lose 80% or more of dopamine in a key area of the brain, noted Dr. Langston. However, evidence suggests that only about 60% of the cells are lost. “That means there are a lot of cells in there that are still alive but probably not making dopamine; they’re not carrying their weight,” said Dr. Langston. “If you could somehow rejuvenate those cells with a trophic factor, a growth factor, you could [attempt to] bring the patient right back out of the clinical range so they would be asymptomatic. There’s a biologic rationale that this could be a very exciting therapy. So in the long term, to get GDNF into the brain, you’re going to have to go to something like in vivo gene therapy. The molecule is too big to get from the blood to the brain. It’s still a challenging area, and even there you have to worry about side effects,” said Dr. Langston. For example, if the patient gets too much GDNF, then the brain goes into overdrive again and start overproducing dopamine. “So the technical barriers are not trivial. Nonetheless, I think it’s probably the leader in terms of something that may be a major long-term benefit for patients,” he said.

Dr. Bronstein noted that GDNF has been the most effective trophic agent for dopaminergic neurons in the laboratory. It has been successfully used in several animal models and by a number of investigators. “An open-label trial in humans resulted in exciting results,” said Dr. Bronstein. “The mode of delivery to the appropriate cells has been the main obstacle in human trials.” The original trial in humans delivered GDNF into the ventricles of patients with advanced Parkinson’s disease. “Although this is OK for a safety trial, as it was billed, it was doomed to fail as an efficacy trial,” Dr. Bronstein continued. “Animal studies had previously demonstrated that animals with less damaged striatums responded better to GDNF than animals with almost total dopaminergic cell loss, as is usually the case in patients with advanced Parkinson’s disease. The drug was delivered into the ventricle, and little drug made it to the target tissue. Thus, very small amounts of GDNF made it to the target in patients that had very few cells left to save. The recent intraputaminal infusions have improved delivery to the proper structures. If these infusions are found to work in properly controlled trials, other more convenient means of getting the drug to the target may allow for the widespread use of GDNF therapy. For example, gene therapy has shown great promise in nonhuman primates and could be utilized in the not so distant future if the current gene therapy trial using glutamic acid decarboxylase proves to be safe and effective,” he said.

GENE THERAPY

Recently, the New York Weill Cornell Medical Center became the first group to administer Parkinson’s disease gene therapy to a human patient, which Dr. Langston referred to as “a brave new world. It’s something that’s not been done before, and it’s got a lot of unknowns. On the other hand, I think intuitively it’s an extremely attractive way to go.… In vivo gene therapy is probably the best chance of getting these growth factors secreted and being made in the area where we need them.… We’re trying to engineer cells to do something that God didn’t plan for them to do. I think there are so many unknowns there you have to be very cautious, but I think the potential is tremendous.”

On the subject of gene therapy, Dr. Bronstein added, “I do not think that increasing gamma-aminobutyric acid production will be an important treatment, but it is a great proof of principle experiment,” he said. “Gene therapy will hopefully be useful in delivering restorative agents such as GDNF.”

NEUROPROTECTION

“Where I’m putting all my money right now, and it’s not such a great thing for people with advanced disease, is in neuroprotection,” said Dr. Langston. “There’s a huge amount of interest right now in trying to find new neuroprotective strategies.” Typically, the average time from first symptom to diagnosis is two years. “What that tells you is that patients are still fairly functional in the early stages of illness,” he said. “It’s very different from stroke, where the barn door is open and the horse is gone.”

In a trial conducted last year, Clifford Shults, MD, of the University of California, San Diego, and colleagues found that coenzyme Q10 slowed by 44% the progression of Parkinson’s disease when given as an oral supplement. Dr. Bronstein remarked that coenzyme Q10 is “promising for some patients to slow but not stop the disease. Neuroprotective and neurorestorative therapies are the best hope for long-term improvements in quality of life since they will address nondopaminergic symptoms.”

With coenzyme Q10, the concept is to slow the progression, echoed Dr. Langston. “I’m a real fan of that, because it came out of some very clearly thought out and elegant basic science, where we found that Parkinson’s patients had a mitochondrial deficiency,” he said. “That came out of the MPTP discovery, and this improves mitochondrial function. And it was based on some very nice animal studies showing that coenzyme Q10 could be neuroprotective in animal models. The study that Cliff Shults published last year, which shows preliminary evidence that it may slow progression of diseases at higher doses, is very encouraging. We’re not recommending that patients take it right now, because that study was not definitive. We need a larger trial to prove it beyond a doubt.

“In the next 10 years, I hope and pray that we will come up with some type of agent that would slow or halt progression, because I think that would have an enormous impact,” said Dr. Langston. “And I think the odds of that happening may be a little greater than finding a cure.”

DRUGS AND OTHER TREATMENT OPTIONS

A variety of medications and treatment options provide relief from the symptoms of Parkinson’s disease, including anticholinergics and amantadine. Bromocriptine, pergolide, pramipexole, and ropinirole all mimic the role of dopamine in the brain. However, levodopa is still considered the gold standard for treatment. First introduced in the 1960s, it delays the onset of debilitating symptoms and allows the majority of parkinsonian patients to extend the time in which they can lead normal, productive lives. However, its side effects include dyskinesias, as well as nausea, low blood pressure, involuntary movements, and others.

As for the future of levodopa in the next decade or so, Dr. Bronstein said, “I do not think levodopa will be the best hope for symptomatic therapy. [Instead, therapy] will utilize more continuous dopaminergic stimulation using new delivery systems and surgery.” As for other drugs and treatment options, Dr. Bronstein said that newer agents “are not all that promising in making a big impact.” He believes that fetal transplants offer little potential, but other transplants, such as retinal pigment epithelial and stem cells, may provide benefit for dopaminergic symptoms.

“I think deep brain stimulation is at least an interim godsend for us,” Dr. Langston said. “It does seem to be effective in certain selected patients. It is useful when you run out of therapeutic options with current pharmacotherapy. I don’t think it’s a long-term solution to Parkinson’s disease for a lot of different reasons, including just the aesthetics of having a piece of metal in your head and your chest. Right now it gives us an option when patients are having so many side effects that we are having trouble managing them medically. For the moment, and I don’t know whether it’s for the next 10 years, deep brain stimulation has provided us with a last resort when patients are no longer doing well with the current drugs we have.”

THE POLITICS OF RESEARCH

One of the early concepts of attempting to find a cure for Parkinson’s disease centered on cell replacement therapy. The first experiments began with human fetal cells, which was very controversial. “Ronald Reagan knocked us out for about eight years with his moratorium on the use of human fetal tissue for transplantation,” said Dr. Langston. “But there’s now been two major studies published using fetal dopaminergic cells from fetal mesencephalon transplanted to humans. We had been very hopeful that this would be something approaching a cure. The idea is you take these dopamine cells—the ones that die in Parkinson’s disease—and you get new cells from aborted fetal tissue and transplant them into the brain in the area where the dopamine is missing. And those cells will grow and thrive and replace the missing dopamine and cure the Parkinson’s disease. Both those trials basically failed. Neither of them showed substantial clinical benefit. Even worse, in both studies some patients had an unacceptable side effect, and that is dyskinesias.… You can see the dilemma—minimal, if any, benefit and high risk. That’s not a good formula for going forward.”

Another problem is that the stem cell work is based on all of the basic principles from fetal cell research, noted Dr. Langston. “I regard this as a major setback to the field. It turns out that we were terribly naive in thinking we could just put some cells in there and it would automatically rewire the nervous system appropriately. In retrospect, I kind of compare it to trying to rewire a house after it’s built, with just walking in and dumping a handful of wires in, say, the living room. So I think we’re headed back to the lab there. I don’t think that [line of research] should continue in patients until we sort it out, both side effects and efficacy. There’s probably just a lot of real basic biology in terms of development that we need to learn before we’re going to succeed at that sort of transplantation. Unfortunately, I think the field has lost ground in this area, and we really need to go back to the lab.”

TIMETABLE FOR PROGRESS

How realistic is it to predict when at least the cause of Parkinson’s disease will be found? “I’ve learned bitterly not to predict times, but I really think in the next 10 years we’ve got a shot at it,” said Dr. Langston. “I think with a full-court press—adequate funding and good science at both the broader levels and the more focused laboratory research—it’s conceivable we could get there in 10 years or less.” As for a cure, “That’s a lot tougher,” he said. “[Because of] the setback in the fetal transplant work and cell replacement work, I see that as a really long haul. If we get a quick hit with growth factors, then I would say the timetable could move up a lot. But when you get beaten up enough, you tend to be cautious.”

Also noteworthy, said Dr. Langston, is that with the discovery of synuclein, which came out of finding one of the rare genetic forms of Parkinson’s disease, and the fact that synuclein is a major component of Lewy bodies, Parkinson’s disease for the first time is being viewed as a possible protein aggregation disorder. “If you believe that, where proteins aggregate and it becomes difficult to reverse and they ultimately damage the cells, it enters an increasingly large pool of diseases, the most famous of which is Alzheimer’s,” he said. “The shift I’ve seen with that change is that a lot of very bright scientists who have many years of experience in protein aggregation, because they’ve been studying the amyloid plaques associated with Alzheimer’s disease, are coming into the Parkinson’s field. I think that’s very exciting.”

In all practicality, said Dr. Langston, “The true cure would be to replace missing cells that die in the brain and do it in a way that is functionally significant. What we’ve learned in the last couple years is that that is going to be a lot harder than we thought. Partial reversal could come from growth factors. I think one of two things is going to happen there—either we’re going to find out very quickly that they really work, and I think that could happen in the next couple years.… If it’s a hit, I think things could be revolutionized. But if it’s not, then my guess is we’ll wind up not giving up on it but saying, ‘Wow, there’s a lot of basic science we have to do before we really understand how to use this and how it works.’ That leads us into gene therapy, because if it really does work with the infusions, which I don’t think you could do in a large number of patients over the long term, then how far is in vivo gene therapy going to get us? Is it really going to work? Is it not going to have safety issues that we can’t overcome or overprotection issues that we can’t control? There are a lot of steps there, but if we get a big hit on that one, I think it will change the landscape.”

NR

—Colby Stong

Suggested Reading
Chen R, Gosavi NS, Langston JW, Chan P. Parkin mutations are rare in patients with young-onset parkinsonism in a US population. Parkinsonism Relat Disord. 2003;9:309-312.
Intemann PM, Masterman D, Subramanian I, et al. Staged bilateral pallidotomy for treatment of Parkinson disease. J Neurosurg. 2001;94:437-444.
Tanner CM. Is the cause of Parkinson’s disease environmental or hereditary? Evidence from twin studies. Adv Neurol. 2003;91:133-142.
Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an etiologic study. JAMA. 1999;281:341-346.

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