A bold, but also much-criticized, experimental therapy for Parkinson's disease involves injecting dopaminergic, human embryonic neurons into a dopamine-depleted brain area of patients in the hopes that the grafted cells will replenish the missing neurotransmitter. Today at the Neuroscience meeting, Curt Freed of the University of Colorado, Denver, and David Eidelberg of North Shore-Long Island Jewish Research Institute told reporters about the long-term follow up of 40 patients.
First off, it is important to note that this treatment cannot become widely available unless the scientists find another source of transplant material. They are now using neurons from only two embryos as opposed to the four fetuses per patient that were needed when this therapy began but, ultimately, a continuous supply of neurons or stem cells from a cell line would be needed. At the same time, however, the procedure is perhaps the most advanced of many experimental cell therapy approaches currently underway and as such offers insight into the prospects of this field. Some patients have been observed for up to seven years.
In a widely noted paper in the New England Journal of Medicine published last March, Freed and his colleagues reported an interim analysis of 40 patients (Freed et al. 2001). They were enrolled in 1994; since then 22 more have had the operation, all without immunosuppression. While the transplants did reverse symptoms in some patients, five had severe, persistent involuntary movements called dyskinesia that arose years after cell implantation. Eidelberg used PET imaging to compare dopamine activity in these five patients to that in patients who did not have dyskinesia.
Eisenberg reports here that his group detected excessive dopamine activity in the dyskinesia patients. The implanted cells effectively overdosed them. Eisenberg et al. also found that these patients had a much greater loss of dopamine transmission (75 percent) in the dorsal, or upper, part of the putamen (the olive-shaped part of the striatum that received the transplant) than in the ventral part (30 percent.) That, Eisenberg said, explained the dyskinesia as the initial 40 patients had received injections into both parts of the putamen. Future transplant patients will receive smaller numbers of cells and only into the dorsal part of the putamen.
How bothersome is this side effect? Do patients regret having had the procedure? Eisenberg said that of the five patients he studied, three considered it acceptable since they had had such movements prior to surgery. For two patients, however, who have severe involuntary movements of the mouth and head, the side effects appear to overshadow the benefits of the transplant.
This raises the question whether this expensive treatment offers any improvement over drug therapy if it generates the same side effects, as does L-dopa. Moreover, L-dopa, which is known to generate schizophrenic side effects when given in excess, can easily be adjusted. How about the transplants? They keep growing and changing over time. Can they be controlled?
Freed noted that the patients in this first controlled trial of CNS transplantation no longer responded well to L-dopa treatment prior to transplantation. After transplantation, they gradually were weaned off L-dopa, and they improved. Those whose transplant released too much dopamine even after they were off L-dopa were successfully treated with a second drug that interferes with dopamine, he said. Those who needed still further reduction of dopamine activity in the putamen (two of the five) were treated with deep brain stimulation, a dopamine-lowering surgery that activates a separate, dopamine-inhibiting brain area. This means that the transplants' effects followed a dose-response curve and can therefore be modulated by more targeted transplantation and subsequent pharmacological management, Freed said.
In Parkinson's, dopaminergic neurons in the substantia nigra that project to the striatum gradually die. In fact, about 80 percent are lost by the time most patients get diagnosed. This creates a dopamine deficit in the putamen and caudate subareas of the striatum. Some dopamine, however, is also made in the frontal cortex and, indeed, Parkinson's frequently progresses from being primarily a movement disorder to becoming a dementing disease (see story below). Freed noted that a paper under submission will report that transplantation had no effect on cognition in his patients.—Gabrielle Strobel
References: Ma Y et al. Dyskinesias following dopamine cell implantation for Parkinson's disease are related to increases in putamen FDOPA uptake. Soc Neuroscience 2001.
Freed CR et al. In double-blind trial, L-dopa responsiveness and not age predicts outcome of human embryonic dopamine cell transplants for Parkinson's disease.
No Available References
- Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med. 2001 Mar 8;344(10):710-9. PubMed.