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Assessing a New Generation of Potential Anti-Parkinson Treatments

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

Neuroprotection, neurorestoration, GDNF, gene therapy, stem cellsÖthe buzz words that express our hopes for a new generation of Parkinson's treatments. What are these strategies? Will they work? What are their limitations? Which patients will benefit from them? And lastly, are there ongoing clinical trials to assess their safety and efficacy? In the following paragraphs we will address these questions.

Neuroprotection vs. neurorestoration

Some new strategies for PD offer the hope of preventing the death of dopamine-producing neurons in the area of the brain called the substantia nigra. These are the cells that are most affected by PD. They project to different areas of the brain, including the striatum, an important center for control of movement. The goal of neuroprotection is to protect the remaining healthy neurons. With restoration, the goal is to enhance the function of remaining neurons to replace lost cells.

PD symptoms become evident when 50 percent of dopaminergic neurons, and 80 percent of striatal dopamine, are lost. Because we cannot yet predict PD in advance, our best alternative is to apply neuroprotective strategies as early as possible in the course of the disease. Early diagnosis using specific batteries of tests may prove extremely helpful in positioning neuroprotective treatments.

Why are neuroprotective strategies so exciting? Because instead of waiting until the damage is done, they aim to head off the progressive loss of the dopamine neurons and its consequences. Many of the problems associated with PD are observed only after years of disease when the neurodegeneration has progressed. Neuroprotective properties have been described for a number of compounds, including Coenzyme Q10, some anti-inflammatories, and dopaminergic agonists.

Glial-derived neurotrophic factor (GDNF)

Scientists have recently been focusing their attention on a nerve growth factor named glial-derived neurotrophic factor, or GDNF.

GDNF, produced by brain cells during the process of development, acts on several nerve populations, and is especially important for dopaminergic neurons. Basic laboratory research using GDNF has provided a body of evidence to support the theory that GDNF has neuroprotective properties, as well as providing some restorative action.

To be effective, GDNF requires long-term, direct delivery to the brain. The first clinical trial with GDNF failed because not enough GDNF reached the substantia nigra and the striatum. A subsequent trial, in the United Kingdom, employed a different delivery system, using tiny pumps placed under the skin. After one year, patients showed encouraging improvement in parkinsonian signs, and a decrease in the incidence of dyskinesias. Clinical trials in the U.K. and the U.S. are ongoing.

Because GDNF treatment is mainly a neuroprotective strategy, scientists predict that it is best suited for patients in the early stages of Parkinson's-that is, those who have sufficient numbers of neurons left to be protected. GDNF delivery requires brain surgery to place the catheter and pump. There is a slight risk of complications, such as infection. On the other hand, an advantage of this continuous direct delivery by pump is that if dosing complications should occur, GDNF administration can be easily, promptly and completely stopped.

Alternative trophic factors, such as neurturin, are now being tested and we expect to learn more in the near future about their app-licability to Parkinson's.

A major challenge of trophic factor approaches is making sure that the compound reaches its target areas in a steady, sufficient amount, without affecting additional areas of the brain. An alternative to this approach-one that also ensures continuous on-site delivery of the therapeutic compound-is gene therapy.

Gene therapy for PD

Gene therapy is the method by which a gene is introduced inside a cell using a "vector"(usually a modified virus that cannot cause disease) that can gain access to the cell. There are two kinds of gene therapy: in vivo, where the vector carrying the treating gene is introduced directly into the brain cells, and ex vivo, where the vector is first introduced into cells outside the brain and then those cells are placed into the brain. In both strategies, the new gene becomes part of the brain cell DNA. In principle, gene therapy can be used for any known gene, but there are practical limitations at this moment, depending on the type of vector and the size of the DNA sequence being used. Safety is a major concern for viral vectors. Researchers are concerned about potential toxicity of a viral vector, how the brain will respond to the viral vector and how we can regulate the product of the new gene.

Candidate genes that may help in the treatment of PD include genes for the enzymes involved in dopamine production. One example of this is the gene for an enzyme known as amino-acid decarboxylase, or AADC. AADC transforms levodopa (the main ingredient in Sinemet) into dopamine (DA). The investigators believe that by delivering the AADC gene to brain cells, they can increase the supply of dopamine.

Another gene therapy approach involves the gene for glutamic acid decarboxylase (GAD). This enzyme metabolizes a chemical named glutamate, which is overactive in a region of the brain in Parkinson's disease. One trial to test the safety of this approach is currently underway.

Stem cells

Stem cells are self-renewable primitive cells that have the potential to transform into neurons, as well as other body cells. Stem cells can be obtained from embryos (embryonic stem cells) or bone marrow. Neural (brain) stem cells and neural progenitor cells are stem cells that have matured one step forward towards becoming brain cells, but they have limited renewal capabilities. Few neural stem cells and neural progenitor cells can be found in the adult brain. Some investigators propose that they can be stimulated to respond after injury, and contribute to brain "self-repair". However, in humans and monkeys, this possibility seems to be far-fetched, because of their scarcity and anatomical issues that make it difficult for the cells to migrate to the areas of the brain where they are needed.

Transplantation seems to be the most viable option for the delivery of stem cells. Similar to fetal tissue transplantation, the process of stem cell transplantation aims to replace the lost DA nigral neurons. Stem cells hold the promise of a source of dopaminergic neurons that can be maintained indefinitely and be widely available. However, these cells retain the ability to differentiate into all tissues and may form tumors (called teratomas) made of a mixture of different types of cells at the implantation sites. The success of future clinical trials will depend on further progress in the research, focusing on understanding what makes a nigral dopaminergic neuron different from other dopamine producing cells.

There are other candidate cells in the body that can produce dopamine, such as the pigmented cells of the retina and the glomus cells in the carotid artery. These cells act mainly by pumping dopamine into the areas where it is needed. A clinical trial for retinal cells obtained from cadavers is currently ongoing in the U.S. and auto-transplant of glomus cells (obtained from the same patient) is being studied in Spain.

In addition to developing new neuroprotective and neurorestorative therapies, combinations of these different strategies are being studied. Combined approaches include delivery of trophic factors and transplantation at the same time, or the use of gene therapy to increase transplanted cell survival or differentiation. Stem cells can also be used for ex vivo gene therapy as a means to deliver candidate gene products into the brain, which could decrease the risk of direct viral vector introduction into brain cells.

The list of potential therapies for PD is long, which is something good. All patients are in different stages of the disease and have different problems that affect them the most, which means that treatments should be tailored to their needs. Although these new approaches are in the earliest stages of development, they have created excitement and hope among scientists and patients alike.

Marina E. Emborg, M.D., Ph.D., is an assistant professor of neurological sciences at Rush University in Chicago. Her research is focused on understanding neurodegeneration in order to develop and test novel neuroprotective and restorative strategies, mainly for the treatment of Parkinson's disease. Rush University Medical Center is a PDF Parkinson's Research Center.