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A New Generation of Anti-Parkinson Treatments: Are We There Yet?

By Marina Emborg, M.D., Ph.D.

In the Spring 2004 issue of News & Review, we reviewed a variety of potential new treatments for Parkinson’s disease (PD). Where do we stand with these therapies? How safe are they? Is the emergence of new therapies keeping pace with our increased understanding of PD? In this article, we provide an update on the state of PD treatments.

Gene Therapy

Gene therapy is the method by which a gene (a piece of nucleic acid containing information to produce a molecule of interest) is introduced inside a cell using a “vector” (usually a modified virus that cannot cause disease) that can gain access to the cell. At this time, gene therapies for PD rely on surgery to inject the vector into the brain.

Several genes have already been identified as having the potential to treat PD, and a few of these are being examined in early stage clinical trials.

One being explored is the gene for neurturin, a trophic factor that helps neurons remain alive and healthy. A Phase I clinical trial of neurturin, also known as CERE 120, was successfully completed and a Phase II trial is close to completion.

Another is the gene that produces an enzyme known as aromatic amino-acid decarboxylase (AADC), that in turn transforms levodopa (the main ingredient in Sinemet®) into the neuronal messenger dopamine. Its safety is currently being investigated in a Phase I trial.

A third option is the gene for glutamic acid decarboxylase (GAD), an enzyme involved in the synthesis of the neuronal messenger gamma aminobutyric acid (GABA). People with PD have overactivity in the area of the brain called the subthalamic nucleus. Researchers propose that since GABA has inhibitory properties, injection in the subthalamic nucleus of vectors encoding for the GAD gene (which increases GABA) will restore balance in the PD circuit. A Phase I trial to test its safety has already been successfully completed and a Phase II trial is under way.

As promising as these potential therapies may be, scientists caution that they are not without risks, including the risk of complications and infection that comes with any brain surgery. There is also concern about the potential toxicity of the viral vectors that are used to transport the genes and about the lack of control doctors have over the vectors, once they are injected into the brain. Even if the molecule is doing its job, there could be cases in which a physician would want to stop or slow its production, but would be unable to do so.

Glial-derived Neurotrophic Factor (GDNF)

GDNF — a growth factor that is chemically similar to neurturin, mentioned above — has received significant media attention, both for its neuroprotective promise and for its potential risks. Since it is a naturally occurring substance in the body and has the ability to slow or reverse the loss of dopamine neurons (still seen as the process by which PD occurs), GDNF has been a target of hope and attention in the PD community.

Initial laboratory research showed that GDNF could protect neurons in PD. However, clinical trials showed mixed results. In 2004, the Amgen Corporation, which holds the GDNF patent, halted all trials of GDNF — citing as their reasons concerns about safety and efficacy.

Research since that time has shown that the problem with the GNDF clinical trials may have been not in the molecule itself, but in its delivery. To be effective, GDNF requires long-term, direct delivery to the brain. It cannot be delivered as a pill or an injection. Because of this, many clinical trials employed a technique involving surgical implantation of a pump and catheter system, permitting continuous intravenous delivery of the GDNF to the designated target area of the brain.

Scientists now understand that it is very difficult to ensure that GDNF, delivered in this way, does not spread to areas of the brain outside the target area. Additionally, various trials used different versions of the pump/catheter system, which may be why their results differed. Accordingly, more recent research is studying different dosing regimens and delivery systems.

There is also increasing agreement among investigators that GDNF treatment may be most helpful for people in the early stages of PD — those people who have larger numbers of neurons available to be protected.

As with all treatments, GDNF does involve risks, including those associated with surgery. By contrast with gene therapy, the GDNF approach gives the treating physician the ability to control delivery externally. This means that if a person were to experience complications with the treatment, his or her physician could easily shut off delivery.  Investigators are eager to continue using GDNF and there is new hope that trials may begin again.

Other Approaches to Neuroprotection

Through gene therapy and growth factors, scientists hope to protect remaining healthy neurons in the brain (neuroprotection) and perhaps restore function to some that have been damaged (neurorestoration). These strategies would be much more proactive than the treatments that are currently available.

Scientists are currently testing the neuroprotective qualities of two nutrition supplements that also play a role in cell energy metabolism. The NET-PD (Neuroprotection Exploratory Trials in Parkinson’s Disease) study is a randomized, double-blind trial studying the potential of creatine and was launched in 2007. There is also an upcoming Phase II trial for Coenzyme Q10 (CoQ10), a naturally occurring substance in the body that plays a key role in the function of the mitochondria, the part of a cell that generates its energy.

Cell-based Therapies

Stem Cell Therapies

Stem cells are primitive cells that have the potential to transform into other types of body cells. Scientists see promise in stem cells for people with Parkinson’s because they could be transformed into neurons, replacing the ones that have been lost or damaged by PD. Types of stem cells include those derived from human embryos (the most versatile), those derived from bone marrow, and those known as adult neural and neural progenitor cells.

Researchers believe that stem cell treatments for Parkinson’s might be best delivered by transplantation, which requires brain surgery. However, this approach presents challenges. Once stem cells are injected into the body, they can form tumors, called teratomas. Another problem is that because the transplanted cells are recognized by the body as foreign, they can come under attack by the body’s own immune system.

To address the latter problem, researchers are working to develop new combinations of immunosuppressants, medications that could decrease immune system attacks. They are also exploring the exciting potential of a recent discovery of stem cells that are derived from a person’s own skin cells and can be reprogrammed to behave like embryonic stem cells. These cells would be free of the immune response problem, because they would be “personalized” — matching the DNA of the person being treated.

Stem Cell Alternatives

Other cells in the body, such as pigmented cells of the retina and glomus cells in the carotid artery, are also seen as potential sources of dopamine. Scientists are looking to these as potential treatments that would work mainly by pumping dopamine into areas where it is needed.

In one study, scientists are investigating retinal cells obtained from cadavers. A Phase I safety study has already been completed, and a double-blind placebo-controlled trial is now underway. In another study, scientists investigating the auto-transplant of glomus cells (obtained from the patient him- or herself) have observed improvements in PD symptoms.

Looking for Safe, Global Therapies to Prevent PD Progression

Many of the therapies mentioned in this review aim to treat the symptoms of Parkinson’s by replacing or protecting the dopamine neurons in the substantia nigra. However, scientists are increasingly realizing that a full explanation of PD’s complex symptoms requires investigation of other areas of the brain. This leads many of them to conclude that halting PD’s progression may require therapies that would address these other areas.

One response to this understanding is to assess the potential of molecules that target cell metabolism. For example, when scientists noted an association between high blood levels of urate (a salt in the body) and lower PD risk, they began studies to assess urate’s neuroprotective potential. Other scientists have suggested that the polyphenols that are found in vegetables and brightly colored fruit — that show antioxidative activity — may have implications for the treatment for PD. New research also points to exercise as a low-risk, high-gain treatment to help slow PD progression. For those people with PD who also have diabetes, it is interesting to note that pioglitazone, an antidiabetic treatment with anti-inflammatory properties, has shown neuroprotective properties in animal studies.

Scientists are also looking for ways to more easily administer existing and potential PD treatments. Currently, treatments such as gene therapy and GDNF require surgery because the molecules involved are too large to cross into the brain by themselves. Some researchers are looking to develop alternative transport systems that would allow these big therapeutic molecules to cross the blood brain barrier without recourse to surgery.


Which of these therapies will be “the” next PD treatment? We don’t yet know, but what we do know is that there is unlikely to be a single “silver bullet” in the fight against Parkinson’s.

The good news is that the ingenuity of investigators has led to the discovery and testing of candidate therapies on several fronts — which is what we need to more effectively treat PD. And that’s something to be excited about.

Marina E. Emborg, M.D., Ph.D., is Director of the Preclinical Parkinson’s Research Program at the Wisconsin National Primate Research Center and an Assistant Professor of Medical Physics at the University of Wisconsin-Madison. Her research is focused on understanding neurodegeneration in order to develop and test novel neuroprotective and restorative strategies for the treatment of PD.