Fetal Neural Transplantation as a Treatment for Parkinson's Disease
Writer’s comment: As a student majoring in biochemistry, I never thought neuroscience would inspire me so greatly. A video shown in my NPB class revealed the devastating effects of Parkinson’s Disease and motivated me to do further research. After talking to my professor, Charles Gray, and reading several papers and books, I realized that there are promising surgical treatments—one of them fetal neural transplantation—with the potential to relieve PD symptoms and improve the quality of patients’ daily lives. Though it may take years or decades before this procedure becomes common clinical practice, it gives millions of Americans with PD (and their families) a good reason to hope. I am grateful to Dr. Gray for his inspiring lectures and guidance; to my English instructor, Anne Fleischmann, for her willingness to help me become a more confident writer; and to Palma Lower (Learning Skills Center) for encouraging me to submit this paper to Prized Writing.
- Jocelyn Lee
Instructor’s comment: The literature review summarizes and assesses recent research on a specific medical question or issue. Jocelyn chose to explore her deep interest in neuroscience and came upon the question of whether fetal neural transplantation offers hope as a treatment for Parkinson’s Disease. Jocelyn’s command of medical terminology and her understanding of the complex processes of Parkinson’s disease and its treatments are remarkable. Indeed, the success of this highly technical paper lies in its clear and engaging style; strong verbs and clearly described cause and effect sequences make the research on fetal neural transplantation seem dramatic and dynamic.
- Anne Fleischmann, English Department
Nearly two centuries after its discovery, the cause of Parkinson’s disease (PD), a chronic neurodegenerative disorder, continues to remain a mystery. PD currently affects about one out of every 100 people over the age of 60, and about 40,000 new patients are diagnosed every year (1). The cardinal symptoms of the disease include resting tremor, rigidity, and bradykinesia, which result from the loss of dopaminergic neurons in the Substantia Nigra and consequent dopamine depletion in the caudate and putamen. As yet, there is no medical treatment that can stop or reverse the degeneration of the nigral neurons. Although the patients can temporarily benefit from L-dopa, a precursor to dopamine synthesis, approximately 60% of patients exhibit severe negative side effects within 5 to 10 years, such as dyskinesia, and “on-off” phenomena (2). The unsatisfactory outcome of drug therapy has led to a search for new treatments that may slow down PD progression and provide lasting control of the symptoms.
Over the years, several neurosurgical operations for the treatment of PD have been proposed, including neurotransplantation. Studies in animal models have shown that grafted embryonic dopamine neurons not only survive in the brains of rats and monkeys, but also form synaptic contacts with host neurons and even restore normal motor function in these animals (1). These promising findings have encouraged researchers to perform clinical trials on humans using cells from aborted fetuses. Since the first clinical trials were initiated in 1987, more than 200 patients with PD have received fetal neural tissue implants throughout the world (2). So far, results from clinical trials are encouraging, with data demonstrating long-term graft survival in human brains and long-term symptomatic relief in some patients (3,4). Nevertheless, there is still no consensus on some fundamental questions regarding optimal donor age, amount of tissue required, optimal site of implantation, patient selection, and the use of immunosuppression. Several researchers have proposed ways to enhance graft survival (5) and increase the availability of the procedure by replacing fetal tissue with alternative tissue sources such as xenograft (6).
This review will highlight the clinical results and surgical criteria that are associated with present transplant procedures and will discuss the improvements that are still required before this treatment can become a common clinical therapy.
Results from Clinical Trials
Long-term graft survival studies have shown that grafted dopamine neurons can survive and grow in the human brain. By utilizing positron emission tomography (PET), which uses radiolabeled neurochemicals as tracers to measure the degree of uptake of certain chemicals in the brain, investigators can determine the effect and objectively measure the results of transplant therapy in humans. In the case of PD, the tracer is usually fluorodopa (F-dopa) because it is an analog of L-dopa, and it can be taken up across the blood-brain barrier and stored in the striatum. Increased striatal F-dopa uptake on the PET scan usually indicates graft survival and successful reinnervation of the host striatum (7). Wenning’s research group reported a 68% increase of F-dopa uptake in the grafted putamen from six patients 8-12 months after transplantation, indicating reproducible dopamine graft survival can be achieved with current transplantation procedures (3). Two patients from Lindvall’s research group even showed a high level of F-dopa uptake in the grafted putamen 6 years after surgery, suggesting that long-term graft survival and function is possible in ongoing degenerative PD patients (4).
Long-term Symptomatic Relief
Patients undergoing fetal neural transplant usually present clear therapeutic improvement. Lindvall’s research group noted that after a delay of 2-3 months when patients had an initial worsening of PD symptoms, they started to improve. “On” time without dyskinesia increased significantly, which relates to the presence of abundant dopamine expressed on grafted dopamine neurons. There were trends for decreased “off” time, suggesting that grafted fetal dopamine neurons have the capacity to convert L-dopa to dopamine and to exert effects over a longer period of time than host dopamine-producing neurons. Tremor did not change in most patients; however, rigidity and the quality of movement improved significantly on the side of the body contralateral to the transplant (2). Long-term functional effects have also been observed on one patient from Lindvall’s group. “On-off” fluctuation, slowness of movement, and rigidity almost completely disappeared on the side contralateral to the graft, and L-dopa was withdrawn 32 months post-surgery. F-dopa uptake was normal in the grafted putamen for 6 years; however, during the 6th postoperative year, there was a moderate worsening of PD symptoms (4). One might suspect that despite the continuing improvement induced by the graft, the progressive PD itself might cause further degeneration of the patient’s remaining dopamine neurons. Therefore, grafts can give rise to long-term therapeutic effects, but the symptomatic relief is incomplete.
Surgical Criteria/Optimal Fetal Age
Animal experiments have shown that donor age is of crucial importance for the survival of grafted fetal tissue. Neural tissues have to be immature in order to survive transplantation because of their better resistance than adult nervous tissue to the lack of oxygen. The optimal human fetal age is from 6.5 to 9 weeks postconception; fetal tissue older than 12 weeks does not survive transplantation in significant quantities (2).
The Amount of Fetal Neural Tissue Required
A normal adult contains approximately 500,000 dopamine-producing neurons from the Substantia Nigra, and the symptoms of PD develop only after a loss of 60- 80% of those neurons. Improvements after transplantation are dependent both on the number of surviving grafted dopamine neurons and the volume and density of reinnervation in the dopamine-deprived striatum. Unfortunately, only 15 to 20% of grafted neurons (about 20,000 to 25,000 dopamine cells) survive from each embryo transplanted. Therefore, some investigators have argued that tissue from 6 or more donors is required in order to restore a satisfactory level of dopamine-producing cells (1). However, the optimal volume of tissue required to transplant for each patient is still not clear.
Optimal Site of Implantation
Also controversial is the question regarding the best site of implantation. Some investigators have transplanted tissue into the putamen because dopamine depletion is most severe in this structure. Besides, the putamen has greater influence on primary motor control than does the caudate. Thus, implanting into the putamen could theoretically have more beneficial clinical effects. Indeed, as indicated by Lindvall, there is no PET evidence so far of dopaminergic graft survival in the caudate, suggesting that the putamen might be a better site for transplant (2). Hawser et al. also noted that functional recovery is correlated to graft survival in the putamen in patients who demonstrate mild to moderate improvements (8).
Although PD is typically a disease of the elderly, most researchers are reluctant to perform transplantation in older patients because of increased risk of complications. Clarkson et al. reports that the average age of the patients at the time of transplant is 52, with average disease duration greater than 12 years. Since the onset age of PD is generally 55, and the average age of the entire PD population is 67, the clinical trials have favored younger patients. However, as Clarkson et al. indicated, the statistical data show no relationship between the clinical outcome and the age at the time of transplant (1). Moreover, only patients with idiopathic PD or MPTP-induced Parkinsonism should receive transplantation. Two patients from Lindvall’s research group showed poor functional outcome despite good grafted fetal tissue survival because those patients had dementia and other concomitant medical problems (3).
The Use of Immunosuppression
Researchers are still debating whether the use of immunosuppression is necessary to prevent the rejection of fetal neural grafts. The brain has been described as an immunologically privileged site because of its lower sensitivity to recognition and rejection of graft tissue. In most clinical cases, immunosuppression was still used when multiple fetal donor tissue was transplanted. However, immunosuppression drugs are not without risks; those drugs largely increase morbidity and mortality from infection. As reported by Madrazo’s group, one patient even developed a brain abscess related to immunosuppressive therapy (2). Currently, researchers have shown that withdrawal of such therapy 6 months to 3 years after transplantation did not interfere with graft survival (3). Thus, researchers believe that long-term immunosuppression is not necessary, but they still do not know whether short-term usage of such therapy is necessary for graft survival.
Graft Survival Rate
Since the amount of graft tissue surviving is one of the critical factors that determines the level of functional improvement, researchers have tried to promote dopamine neuron survival after transplantation. In a recent case study, Sinclair et al. suspected that toxic changes in the host environment within the first hour after injury might be responsible for the poor survival of grafted dopamine neurons. The authors hypothesized that if one or several acute changes, such as a fall in pH, in the host environment induced by injecting cannula are toxic to the grafts, delaying extrusion of the graft tissue until toxic changes return to normal (i.e. approximately 1 hour after lowering the injection cannula) should enhance graft survival. They tested the hypothesis by using twenty-four young adult female rats. The consequences of a brief delay (20 minute, 1 or 3 hours) were measured by the number and size of the cells in the striatum after transplantation. The results (Figure 1) showed that a delay of as little as a one hour resulted in a three-fold increase in survival of grafted dopamine neurons (5). Although such delay modification may reduce the efficiency of the procedure, the introduction of an implantation delay nevertheless has provided a potentially powerful strategy to enhance graft survival.
Figure 1. Quantitative measures of graft survival and maturation. (A) Estimated cell numbers in the grafts in each group. (B) Estimated volumes of the cell soma in the grafts in each group. (Adapted from Sinclair et al.)
Alternative Tissue Sources—Xenograft
The use of fetal neural tissues for transplantation has raised ethical concerns and logistical problems concerning tissue supply. Such problems can possibly be solved by using alternative tissue sources, such as xenograft. Recently, Deacon et al. reported that fetal pig neural cells could survive transplantation into a PD patient. A total of 638 grafted dopamine neurons were found at three graft sites in the putamen (6). This finding supports the idea that xenograft may be a potential alternative to human fetal cell transplants. However, xenograft rejection is still an unsolved problem. Both the yield of surviving pig dopamine neurons and the extent of reinnervation in the host striatum have to be significantly increased before this kind of tissue source can be compatible with human fetal neurons.
The complications from current drug therapy for PD have led to a search for new surgical treatments, such as neurotransplantation. Successful studies in animal models have provided the rationale and empirical basis for clinical trials using fetal tissues. Results have shown that long-term graft survival is possible in ongoing degenerating human brains, as reported by Wenning’s and Lindvall’s research groups. Long-term functional effects have also been observed, at least up to six years, in one patient from Lindvall’s group.
Although it has been 13 years since the first PD patient underwent such a procedure, several surgical criteria regarding this procedure are still controversial. Optimal donor age has been estimated to be around 6.5 to 9 weeks postconception, and the putamen is the favored site of implantation rather than the caudate. From results published so far, age does not seem to predict transplant outcome, though patients with major medical problems such as dementia are usually excluded from the studies. The role of immunosuppression and the amount of fetal neural tissue required for optimal clinical benefits remain to be determined.
The long-term survival and function of grafted dopamine neurons in patients represents an important step for transplantation becoming a therapy for PD. However, the relatively poor survival of grafted dopamine cells and the limited availability of suitable donor tissues have to be overcome before such an approach can be regarded as an established treatment. Sinclair et al. introduced a one hour delay graft injection which can yield a significant improvement in graft survival. Alternative tissue sources such as xenograft are currently under investigation. Provided that current research is aimed at enhancing the efficiency of the implantation, and transplantation is performed judiciously under strict adherence to basic principles defined by animal and human experimentation guidelines, more patients will likely benefit from this procedure in the future.
1 Clarkson, ED., Freed, CR. “Development of fetal neural transplantation as a treatment for Parkinson’s disease.” Life Sciences. 65(1999): 2427-2437.
2 Deacon, T., Schumacher J., et al. Nature Med. 3(1997): 350-353.
3 Hauser, RA., Olanow, CW., et al. “Fetal nigral transplantation in Parkinson’s disease.” In Cell transplantation for neurological disorders. New Jersey: Humana Press, 1998.
4 Lindvall, O., Sawle, G., et al. “Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease.” Annals of Neurology. 35(1994): 172-180.
5 Lindvall, O. “Neural transplantation: a hope for patients with Parkinson’s disease.” Neuroreport. 8(1997): iii-x.
6 Sinclair, SR., Fawcett, JW., Dunnett, SB. “Delayed implantation of nigral grafts improves survival of dopamine neurons and rate of functional recovery.” Neuroreport. 10(1999): 1263-1267.
7 Snow, BJ. “PET studies of transplantation therapy.” In Cell transplantation for neurological disorders. New Jersey: Humana Press, 1998.
8 Wenning, GK., Odin, P., et al. “Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease.” Annals of Neurology. 42(1997): 95-107.