Summer 2006

Exploring New Paths for Parkinson's Disease Treatment

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 neuroscientists are taking a multi-pronged 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 etiology of PD is unknown, the idiopathic disease is characterized by degeneration of dopamine-producing neurons in the substantia nigra and a resulting dopamine deficiency in the striatum.

One established treatment for Parkinson's disease is deep brain stimulation (DBS) — the implantation of an electrode in the brain. The electrode is usually placed in the globus pallidus pars interna or in the subthalamic nucleus 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, M.D., Ph.D., Paul S. Larson, M.D., William J. Marks Jr., M.D., and Jill L. Ostrem, M.D. — 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.

One theory about the etiology of Parkinson's disease is that the neurodegeneration is caused or exacerbated by mitochondrial dysfunction. 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 prove neuroprotective of the 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, M.D., Ph.D., and his colleagues, targets the dopamine deficiency directly by introducing a gene for the dopa decarboxylase enzyme, which changes levodopa into dopamine. This approach may address the declining effectiveness of levodopa after long use. The trial is being conducted by UCSF neurologists Michael J. Aminoff, M.D., and Chadwick W. Christine, M.D., 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 dopaminergic neurons by preventing their death, restoring their capacity to synthesize neurochemicals and maintaining or regenerating presynaptic terminals.

In the longer term, Arnold Kriegstein, M.D., Ph.D., Arturo Alvarez-Buylla, Ph.D., 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.

Related Information

News Releases

Parkinson's Disease Expert Wins Grant
Dr. Robert L. Nussbaum, professor of medicine and chief of medical genetics at UCSF Medical Center, received one of seven grants from the Michael J. Fox Foundation for Parkinson's Research to develop mammalian models of Parkinson's disease.

Mechanism Identified for Promising Drug
Researchers at the San Francisco VA Medical Center identified a mechanism by which minocycline, a medication being studied for the treatment of neurodegenerative diseases, protects brain and nerve cells from damage.