Among PD treatments, no therapy has raised greater hopes or stirred more controversy than that of fetal transplantation. Although clinical trial failures have curtailed interest in this therapy, it remains an area of considerable research and discussion. Understanding the work that has been done in this area may be instrumental in guiding future cellular restorative therapies such as stem cell transplantation.
Rodent and primate models of PD have shown dramatic response to the transplantation of fetal cells (48-51). The demonstration of behavioral improvements (52-54) and histological reinnervation of striatal regions by dopaminergic transplants (51) suggested that a successful treatment strategy had been identified. The first human cases of fetal transplantation for PD were reported in 1990 (55,56). Early anecdotal cases reported dramatic benefit. Several of these studies were also able to corroborate observed clinical improvements with PET evidence of increased dopamine uptake or with histological evidence of reinnervation by transplanted fetal cells (57). An open-label study demonstrated significant improvements in each of seven treated patients for 12 to 46 months following surgery. All seven patients demonstrated improvement in activities of daily living (ADLs). Five of the seven patients had significant improvements in UPDRS motor scores. The group also demonstrated medication reductions by an average of 39% (58).
In 2001, a double-blind sham-surgery controlled study was published. Patients treated with fetal transplantation showed no significant difference in the primary outcome measure of subjective self-reported improvement. Neither the treated patients nor the sham-surgery controls reported any subjective benefit. Secondary objective measures, including UPDRS motor scores, were slightly more promising. Treated patients demonstrated an 18% improvement in UPDRS motor scores off medication, compared with no improvement in sham controls. The effect was more pronounced in the group of patients less than 60 years of age, whose scores improved 34%. No additional benefit was accrued in the medication on state in any group. Notably, the study was performed without immunosuppression (59).
The negative results produced by this study after such promising early trials spurred a second double-blind controlled trial. In this study by Olanow et al., 34 patients were randomized to sham surgery, or intraputaminal implantation with one or four grafts per side. Notably, solid mesencephalic grafts were used (as opposed to dissociated cell suspensions) and patients were kept on immunosuppression for a period of six months. Patients were followed for a total of 24 months and the primary endpoint was objective change in the UPDRS motor score. In this study, results demonstrated no significant improvement in either treatment group when compared to placebo. At six months, the treatment groups showed significant benefit compared to controls; however, this effect was gradually lost over the subsequent six to nine months. This suggests that immunosuppression may have an important protective role in cellular therapies. Further subgroup analysis demonstrated that patients with less severe disease (UPDRS motor score < 49) did show significant improvement and that there was further significant benefit to treatment with multiple donors (60).
The blinded studies also demonstrated a significant incidence of graft-induced dyskinesia. This troubling side effect was reported in 15% of patients in the study by Freed et al. (59) and in 58% of patients in the Olanow et al. study (60). It is not clear if this effect is the result of partial reinnervation of immunologic graft rejection producing atypical dopamine release or some other mechanism.
The failure of double-blind studies to demonstrate consistent benefit has curtailed that application of fetal transplantation. However, the apparent success of individual patients and the evidence for substantive reinnervation as demonstrated by histology or by PET imaging have led investigators to identify factors that may contribute to treatment success (61). Several factors seem to have had influence on the results. First, the amount and age of transplanted tissue may be of importance. One group has reported an optimal fetal age of 5.5 to 8 weeks for transplantation (62). Secondly, the handling of fetal tissue prior to implantation may also have a critical effect. This has been evidenced in part by the few patients who came to autopsy. These reports demonstrate significant variability in the extent of striatal reinnervation by transplanted neurons. One study demonstrated a single patient who had derived significant benefit from his transplantation and was found at autopsy to have widespread and confluent striatal innervation with minimal inflammatory reaction (57). Contrasting histological reports demonstrated far more limited survival from fetal transplants that were older or had undergone cryopreservation (63,64). Finally, several studies have examined the necessity of immunosuppression to allow cellular integration of the foreign transplants. The Olanow et al. study suggested that steroid suppression was beneficial up to six months and its withdrawal might account for the subsequent worsening of UPDRS motor scores in transplanted patients. Piccini et al. identified six patients who underwent steroid suppression for more than two years. In these patients, the withdrawal of steroids at an average of 29 months produced no rebound in UPDRS motor scores and no changes in striatal dopamine uptake on PET scanning (61).
These studies demonstrate the extremely tenuous nature of this technique. It may be that the failed transplantation trials resulted from technical sensitivities and not from a failure of principle. This observation provides hope that new cellular-based therapies may be effective if larger numbers of cells can be transplanted or greater cell survival can be achieved.
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