Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease
Curt R. Freed, Paul E. Greene, Robert E. Breeze, Wei-Yann Tsai, William DuMouchel, Richard Kao, Sandra Dillon, Howard Winfield, Sharon Culver, John Q. Trojanowski, David Eidelberg, Stanley Fahn
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The New England Journal of Medicine -- March 8, 2001 -- Vol. 344, No. 10
Abstract
Background. Transplantation of human embryonic dopamine neurons into the brains of patients with Parkinson's disease has proved beneficial in open clinical trials. However, whether this intervention would be more effective than sham surgery in a controlled trial is not known.
Methods. We randomly assigned 40 patients who were 34 to 75 years of age and had severe Parkinson's disease (mean duration, 14 years) to receive a transplant of nerve cells or undergo sham surgery; all were to be followed in a double-blind manner for one year. In the transplant recipients, cultured mesencephalic tissue from four embryos was implanted into the putamen bilaterally. In the patients who underwent sham surgery, holes were drilled in the skull but the dura was not penetrated. The primary outcome was a subjective global rating of the change in the severity of disease, scored on a scale of -3.0 to 3.0 at one year, with negative scores indicating a worsening of symptoms and positive scores an improvement.
Results. The mean (±SD) scores on the global rating scale for improvement or deterioration at one year were 0.0±2.1 in the transplantation group and -0.4±1.7 in the sham-surgery group. Among younger patients (60 years old or younger), standardized tests of Parkinson's disease revealed significant improvement in the transplantation group as compared with the sham-surgery group when patients were tested in the morning before receiving medication (P=0.01 for scores on the Unified Parkinson's Disease Rating Scale; P=0.006 for the Schwab and England score). There was no significant improvement in older patients in the transplantation group. Fiber outgrowth from the transplanted neurons was detected in 17 of the 20 patients in the transplantation group, as indicated by an increase in 18F-fluorodopa uptake on positron-emission tomography or postmortem examination. After improvement in the first year, dystonia and dyskinesias recurred in 15 percent of the patients who received transplants, even after reduction or discontinuation of the dose of levodopa.
Conclusions. Human embryonic dopamine-neuron transplants survive in patients with severe Parkinson's disease and result in some clinical benefit in younger but not in older patients. (N Engl J Med 2001;344:710-9.)
Source Information
From the University of Colorado School of Medicine, Denver (C.R.F., R.E.B., S.C.); Columbia University College of Physicians and Surgeons, New York (P.E.G., W.-Y.T., R.K., S.D., H.W., S.F.); AT&T Shannon Laboratory, Florham Park, N.J. (W.D.); University of Pennsylvania Medical Center, Philadelphia (J.Q.T.); and North Shore University Hospital, Manhasset, N.Y. (D.E.). Address reprint requests to Dr. Freed at the Division of Clinical Pharmacology, C-237, University of Colorado School of Medicine, 4200 E. Ninth Ave., Denver, CO 80262, or at curt.freed@uchsc.edu.
EDITORIAL
Cell Therapy for Parkinson's Disease
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Parkinson's disease is characterized by the progressive loss of dopamine neurons in the substantia nigra of the midbrain. These neurons project widely throughout the cerebral hemispheres, but the motor symptoms of Parkinson's disease -- bradykinesia, muscle rigidity, and resting tremor -- are almost certainly due to the loss of dopamine nerve terminals in the caudate and putamen nuclei (the striatum) of the basal ganglia and the unbalancing of circuits required for coordinated movement. One of the therapeutic successes of clinical neurology has been the use of levodopa, the precursor of dopamine, in patients with Parkinson's disease. In nearly all patients, the reversal of symptoms is truly remarkable. However, dopamine replacement does not slow the rate of loss of neurons, and the beneficial effects wear off with time. Some patients become less responsive to medication; others become hypersensitive, and abnormal movements (dyskinesias) develop. These unsatisfactory outcomes have led to development of dopamine-receptor agonists and surgical approaches that include pallidotomy and deep-brain stimulation of the globus pallidus, the thalamus, or the subthalamic nuclei. (1,2) There have also been attempts to transplant precursors of dopaminergic nerve cells directly into the striatum. (3)
The study reported by Freed et al. (4) in this issue of the Journal is the latest in a series of attempts to treat Parkinson's disease by transplanting precursors of dopaminergic nerve cells in fragments of mesencephalon isolated from human fetuses 6 to 10 weeks after conception. Nearly all previous reports describe moderate improvement in the motor symptoms in a subgroup of patients. These results are remarkable, considering the complexity of the circuits in the striatum and the rest of the basal ganglia and the lack of standards regarding the amount and handling of tissue to be transplanted, the placement (caudate nucleus or putamen; unilateral transplantation or bilateral transplantation), the criteria for the selection of patients, and the duration of follow-up. It is encouraging that some of the implanted cells survive and differentiate, as demonstrated by positron-emission tomography (PET) or by histologic examination.
The trial conducted by Freed et al. is the first prospective study comparing a transplantation group with a control group. In the patients in the control group, burr holes were drilled through the cranium, but the dura was not penetrated and no cells were implanted. The surgical team and statisticians were aware of the treatment assignment of each patient, but the patients and examining physicians were not. The trial also differed from other studies in important technical details. The fragments of fetal mesencephalic tissue were dissociated in a cell suspension, and the cells were maintained in vitro before implantation, perhaps contributing to their survival in vivo in the absence of immunosuppressive therapy.
The use of placebo ("sham") surgery has triggered a spirited debate. (5) Rather than adopt a general policy regarding placebo surgery, one must weigh for each study the safety of such surgery against the importance of the results. The debate should be informed by the realization that the results in the transplantation group in the trial by Freed et al. could not have been interpreted fully without analysis of the control group.
After one year, patients younger than 60 years old in the transplantation group had a small decrease in rigidity and bradykinesia but no change in tremor or gait. Improvement was detected only early in the morning after the patients had been without medication overnight. No improvement was evident when the patients were at their best, soon after a dose of medication. For other outcomes, including the primary one, the score on a global self-rating scale, no benefit was documented at any time of day in any age group. PET studies with 18F-fluorodopa revealed that the transplants contained competent dopamine nerve terminals. However, there was no correlation between these findings on imaging studies and motor improvement.
Disabling dyskinesias appeared in 15 percent of the patients who received implants, but only in the second year after surgery. These severe side effects appeared in the same patients who had improved during the first year after surgery, and they persisted despite the lowering of the dose of levodopa. Dyskinesias were noted in earlier open trials, but they usually subsided when doses of medication were reduced. One of the most important lessons from this study is that one year of follow-up is not sufficient for an evaluation of nerve-cell transplantation. Neural plasticity works at mysteriously different rates, so long-term outcome must be evaluated.
To reach a consensus about therapies involving the implantation of tissue or cells, we must learn more about the circuits within the basal ganglia and their extrinsic connections. (6) Transplanted dopaminergic neurons are said to "innervate" targets in the putamen, but this term is used loosely, since precise measures of synaptic function are not available. We do not know how dopamine affects the firing of individual neurons or the function of particular circuits.
It is unlikely, for both practical and biologic reasons, that transplantation of fragments of embryonic tissue will be the therapy of the future. In the present study, tissue from the midbrain of two embryos was injected on each side of the brain in each patient. Parkinson's disease is not a rare disorder: estimates of prevalence in the United States range between 700,000 and 1 million. The number of fetuses required would be staggering, even if only a small proportion of the patients were to receive transplants. Moreover, heterogeneity within tissue fragments is a major barrier to reproducibility. The Food and Drug Administration will certainly require standardization of the preparations of cells.
Immortalized cell lines are our best hope for the development of cells as realistic and reliable therapeutic agents. The use of cell lines derived from pluripotent human fetal or embryonic stem cells poses profound ethical questions, (7,8) but they are currently the most promising therapeutic possibilities. Successful transplantation of stem cells has already been achieved in animal models of Parkinson's disease, motor neuron disease, and spinal cord injury. Other sources of stem cells, including adult brains and bone marrow, are under investigation, but their ability to proliferate and the diversity of their offspring remain unknown.
To consider the use of transplanted cells as a treatment for Parkinson's disease -- whether they are pluripotent stem cells, more restricted precursors, or differentiated neurons -- we must know more about their molecular composition. In addition to dopamine, such neurons probably manufacture molecules that influence neuronal proliferation, migration, differentiation, and survival. All these functions are at risk in Parkinson's disease. Also, the role of electrical-impulse activity may be important, but we know little about the functional state of the implanted cells. As the present study indicates, mere survival is not enough.
The promise of cell therapies has captured the imagination of scientists, patients, and other members of the public. (9) Symptomatic treatments are available, but we have not yet reversed the course of any neurodegenerative disorder. The brain is a most complex structure, so incremental results on the way to cures are to be welcomed rather than dismissed as less than perfect.
Gerald D. Fischbach, M.D.
Guy M. McKhann, M.D.
National Institute of Neurological Disorders and Stroke
Bethesda, MD 20892
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March 8, 2001
ALL THINGS CONSIDERED (14.4 | 28.8)
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Parkinson's (14.4 | 28.8) -- A paper in today's New England Journal of Medicine reports that treating Parkinson's disease patients by transplanting fetal cells into their brains produced severe side effects in some cases. NPR's Joe Palca looks at what this means for further research. (4:00)
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