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EXPERIMENTAL TRANSPLANT TREATMENTS FOR PARKINSON’S DISEASE
DENVER—Long-term results from fetal cell transplant surgery and promising initial results from two novel procedures suggest that the options for treating late-stage Parkinson’s disease may be expanding. Findings from studies involving experimental treatments were presented at the 54th Annual Meeting of the American Academy of Neurology.
FETAL CELL TRANSPLANTS
Several hundred Parkinson’s disease patients have received transplantation of fetal cells into the striatum, and while most open-label results have been positive, patient series have been small and follow-up generally short. Results from the only double-blind trial to date were less positive, with significant benefit seen only in younger patients. More troubling is that some of these patients developed “runaway” dyskinesias, which, unlike typical treatment-related dyskinesias, occurred while patients were not taking levodopa. A study led by Curt R. Freed, MD, Director, Neural Transplant Program for Parkinson’s Disease, University of Colorado Health Sciences Center in Denver, and Stanley Fahn, MD, Professor of Neurology and Director of the Center for Parkinson’s Disease and Other Movement Disorders at Columbia University in New York City, has shown that the benefits from this procedure continue for at least eight years, and that the runaway dyskinesias can be controlled with subthalamic nucleus stimulation.
Twenty patients received transplants of the embryonic dopamine cells during the double-blind phase of this trial, and 14 more underwent the procedure after the blind was broken. As reported previously, while significant motor improvement was seen in the group as a whole, the benefit was primarily confined to patients 60 years or younger. Dr. Freed presented the most recent data available for 18 patients, including 11 young and seven older patients. The motor effects seen at 42 months were essentially identical to those seen at 12 months, with young but not older patients showing significant benefit. Young patients had an improvement of approximately 30% in their motor score while not taking antiparkinsonian medication, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS). Benefit was seen principally for bradykinesia and rigidity but not for freezing of gait. “The effects of transplants are sustained,” Dr. Freed said. “Our study is really the first with enough patients to be able to draw that general conclusion.”
Regarding factors that predict response, Dr. Freed related that the preoperative response to levodopa—not patient age—is the best predictor of benefit from surgery. “The maximum benefit that can be expected from transplants may duplicate, but not exceed, the best ‘on’ response to levodopa seen preoperatively,” he explained. The previous correlation with age is better seen in this light, he said—older patients generally have a less strong response to levodopa, but those who responded well to medication tended to do well with the transplant surgery.
Dr. Freed also reported that grafts increase their rate of uptake of a dopaminergic marker for a year after transplant and stabilize thereafter. Postmortem brain examination of several patients who underwent transplantation has shown not only that cells survive and integrate but that after several years they begin to accumulate neuromelanin at a rate similar to that seen in normally developing nigral cells.
One untoward response to levodopa was also mimicked as a result of the transplants in five patients who developed dyskinesias even while they were not taking antiparkinsonian medication. This unexpected adverse effect was troubling enough that Dr. Fahn stated in 2000 that he could no longer recommend the surgery until this side effect was better understood. Dr. Freed reported that no new patients have developed dyskinesias, and no worsening of the condition of affected patients has occurred.
Three of the patients have been treated with deep brain stimulation to the subthalamic nucleus. Their response was comparable to that of non-transplant patients who had undergone surgery for dyskinesias, and their symptoms were well controlled by a combination of surgery and medication. Two other patients have been successfully managed by medication alone, including the tyrosine hydroxylase inhibitor metyrosine. Remarkably, one of these patients, an electrician, was on the 34th floor of one of the World Trade Center towers on September 11, 2001. Dr. Freed reported that after the plane hit, this man “walked down 33 flights of stairs, ran five blocks, and walked to Penn Station to take a train home.”
RETINAL PIGMENTED EPITHELIAL CELLS
The early success of an entirely different kind of cell therapy was presented by Ray L. Watts, MD, of Emory University in Atlanta. Dr. Watts and colleagues have been studying the potential benefits of intrastriatal implantation of dopamine-producing cells on inert gelatin microsphere carriers. Derived from pigmented retinal epithelium, these cells have the advantage of remaining on the carriers; indeed, they die if they lose contact with their substrate. Therefore, they are not likely to pose the risk of aberrant integration that some researchers think may be responsible for the dyskinesias seen in fetal cell transplants. Additionally, unlike fetal cells, retinal cells are plentiful and easy to harvest from donated organs.
Dr. Watts and colleagues treated six patients whose mean disease duration was 10.2 years. Each patient received a total of 325,000 cells delivered unilaterally along five tracts to the putamen contralateral to the most affected side of the body. All patients improved in the primary outcome measure, the UPDRS motor score, while not taking antiparkinsonian medication. While most improvements were contralateral to the implanted side, some bilateral improvement was also seen. Loss of dopamine function had slowed by 30% at three months and remained steady for the next nine months. Decreases were also seen in total time spent off antiparkinsonian medication. These improvements did not come at the expense of increased dyskinesia, Dr. Watts noted. Dyskinesias actually improved from baseline in three patients, while they remained unchanged in the other three patients. No treatment-related adverse events were seen. While this was a small study with open-label treatment, Dr. Watts is encouraged by both the safety and efficacy of this approach and is planning additional trials.
DIRECT BRAIN ADMINISTRATION OF GDNF
Glial-derived neurotrophic factor (GDNF) has intrigued researchers for almost a decade. It promotes growth of dopaminergic neurons in cell culture, is neuroprotective in animal models of Parkinson’s disease, and improves motor performance in these models as well. Improvement in primate models has been seen with intraventricular, intrastriatal, and intranigral delivery. However, a double-blind trial of GDNF in patients with Parkinson’s disease that was reported at last year’s American Academy of Neurology meeting demonstrated no improvement in Parkinson’s disease symptoms when GDNF was administered intraventricularly. This year, results from an open-label trial in a small group of patients who received GDNF directly to the striatum were presented—the first time improvement has been recorded as a result of growth factor infusion.
Steven S. Gill, MD, a consultant neurosurgeon, and colleagues from Frenchay Hospital in Bristol, United Kingdom, enrolled five patients who underwent implantation of a cannula to the dorsal putamen, connected to an implanted mini-pump. The pump delivered recombinant human GDNF directly to the brain for one year. Mean total UPDRS scores fell from 66 to 30, a highly significant decrease in disability. These improvements were not accompanied by significant adverse effects. Study coauthor Clive N. Svendsen, PhD, of the Waisman Center at the University of Wisconsin in Madison, noted, “This is the first attempt to deliver a growth factor directly to the brain. As these are large proteins which do not cross the blood-brain barrier, direct delivery is essential.” He suggested that the failure of the previous GDNF trial to produce symptomatic effects occurred probably because GDNF does not easily penetrate brain tissue, even from the ventricles.
“This is a non-blinded phase I study,” Dr. Svendsen cautioned, and so the results must be interpreted with care. Larger trials are being planned now, and he looks forward to learning more about the mechanism by which GDNF exerts its effect. “We are interested in seeing what happens at longer time points,” he said. “This will establish whether GDNF is simply acting to up-regulate dopamine pharmacologically or has long-term effects on dopamine neuronal survival and outgrowth. If the GDNF is simply up-regulating dopamine production, this is of interest as an adjunct to levodopa or dopamine-agonist treatment.” If, on the other hand, GDNF is protecting dying neurons, Dr. Svendsen said, “obviously this is far more exciting. But we must wait for the longer-term phase of the study to establish if brain repair or protection of dying dopamine neurons is really happening.”
NR
—Richard Robinson
Suggested Reading
Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344:710-719.
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