Exploring Many Paths for Parkinson's Disease Treatments

The last few years have produced an impressive store of insights and discoveries in neuroscience, but Parkinson's disease remains particularly resistant to treatment. Parkinson's is an inexorable neurodegenerative disease that can be treated symptomatically, but is still not curable. Currently available medications may lose their ability to provide consistent symptom control, and may produce significant side effects over time. UCSF scientists work together to explore therapies and seek a cure UCSF neuroscientists are taking a multipronged approach to Parkinson's disease, positioning themselves at the forefront of research into therapies that may improve symptomatic treatments and eventually may provide a cure. Neurosurgeons, neurologists, neuroradiologists and basic scientists are working together to conduct clinical trials of medical therapies, surgical treatments and gene transfer therapy, as well as to conduct basic research on the use of stem cells. Parkinson's disease (PD) affects more than 1 million people in North America. Although the primary cause of PD is unknown, the disease is characterized by degeneration of dopamine-producing neurons in the substantia nigra and a resulting dopamine deficiency in the striatum. Dopamine is a compound naturally produced in the body that stimulates the nerve cells that control movement. In PD, the insufficient formation of dopamine noticeably affects movement and muscular control, resulting in tremors, rigidity, impaired balance and other motor symptoms. Deep brain stimulation (DBS) effectively treats some symptoms One established treatment for Parkinson's disease is deep brain stimulation (DBS): the implantation of an electrode in the brain, with the leads connecting to a pacemaker-like device implanted under the skin in the patient's chest. DBS is an effective treatment often used for patients whose symptoms are inadequately controlled by medication. It also has the advantage of being adjustable, reversible and not destructive to brain tissue. Most patients see significant improvements in their "on" time - the time during their day when symptoms are well controlled and function is good. In addition, dyskinesia - the abnormal, involuntary movements that often result from medication overshoot - is usually suppressed. Like medication, however, DBS is a symptomatic treatment that is not thought to slow the progression of the disease. UCSF researchers Philip A. Starr, MD, PhD, Paul S. Larson, MD, William J. Marks Jr., MD, and Jill L. Ostrem, MD, have designed a clinical trial to compare the efficacy of implanting the DBS electrode in one of two brain targets - the globus pallidus or the subthalamic nucleus. The investigators are conducting a double-blind comparison of these two therapeutic targets, in cooperation with five other national research centers. Possible causes, therapies and clinical trials One theory about the cause of Parkinson's disease is that the neurodegeneration is induced or exacerbated by malfunctioning mitochondria, which convert organic materials into energy that cells can use). Last year, the UCSF Parkinson's Disease Clinic and Research Center participated in a national clinical trial of four compounds that may boost the efficiency of mitochondria. This increased mitochondrial efficiency may help protect dopamine-producing neurons in the substantia nigra, and may therefore slow the progression of the disease. This year, one of the four compounds has been selected for a more intensive trial. The last few years have revealed a number of gene mutations associated with familial forms of PD. Researchers now hope that they might be able to directly correct genetic causes of PD, thereby alleviating symptoms, slowing the disease progression and perhaps eventually curing the disease. Gene manipulation has shown promise in animal models, and UCSF scientists are hopeful that promise will be fulfilled in coming human trials. Two gene therapy trials for PD are in various stages at UCSF. Last year, UCSF began a phase I clinical trial of a growth factor called neurturin in conjunction with the company Ceregene. The hope is that dopamine-producing cells in the substantia nigra will survive better with the assistance of neurturin, potentially slowing the progression of PD or reducing its symptoms. A current clinical trial, developed by UCSF investigator Krzysztof Bankiewicz, MD, PhD, and his colleagues, targets the dopamine deficiency directly by introducing a gene for an enzyme critical in the formation of dopamine from levdopa, a drug currently used to treat PD. This approach may address the declining effectiveness of levodopa after long use. The trial is being conducted by UCSF neurologists Michael J. Aminoff, MD, and Chadwick W. Christine, MD, in cooperation with Starr and Larson. Bankiewicz and his colleagues are planning a clinical trial of glial cell line-derived neurotrophic factor (GDNF). The goal of GDNF therapy is to restore function to degenerating dopamine-producing neurons by preventing their death, restoring their capacity to synthesize neurochemicals, and maintaining or regenerating the part of the nerve cell that sends signal on to the next nerve cell. Stem cell research might lead to treatment for PD In the longer term, Arnold Kriegstein, MD, PhD, Arturo Alvarez-Buylla, PhD, and Bankiewicz are exploring whether neural stem cells, which reside in the brain, could someday be used to treat PD. While researchers are still in the early stages of investigating this possibility with human stem cells in the lab, there is some expectation that PD could be one of the first diseases treated in this way. The most common strategy being explored is to implant dopamine-producing neurons derived from rat embryonic stem cells in a rat model of PD. Kriegstein and his colleagues are taking a different tack. Their goal is to correct the imbalance of neuronal activity that occurs as a result of a loss of dopamine in the brain. Their studies, also conducted in rats, focus on a kind of neural stem cell that differentiates into inhibitory neurons. These cells are transplanted into a rat model of PD, where they have a remarkable ability to integrate into the circuitry.