Doubleblind controlled studies to assess fetal nigral transplantation in PD

To better define the safety and efficacy of fetal nigral transplantation as a treatment for PD, the National Institutes of Health in the USA supported two double-blind, placebo-controlled trials. These studies were not without controversy. Some felt it was premature to carry out a double-blind clinical trial, others argued against the use of sham controls for a surgical procedure, and the use of embryonic tissue as a source of dopamine cells remains a controversial topic (Cohen, 1994; Freeman et al., 1999; Macklin, 1999).

The first of these studies was a 1 year trial in which 40 advanced PD patients were randomized to receive bilateral transplantation or a sham placebo operation (Freed et al., 2001). Ventral mesen-cephalic tissue was stored for up to 4 weeks, and solid grafts derived from two donors per side were implanted longitudinally into the putamen using two deposits or "noodles". The sham procedure consists of a burr hole without needle penetration of the brain. Immunosuppression was not employed. The primary endpoint of the study was the change from baseline to final visit in a measure of quality of life. The study failed to meet its primary endpoint, as transplanted patients were not improved in comparison to those in the placebo group (0.0 ± 2.1 on UPDRS in the transplant group and —0.4 ± 1.7 in the sham surgery group). A pre-specified analysis demonstrated a significant benefit of transplantation in younger patients (< 60 years) in UPDRS motor score performed in the practically defined off state (P < 0.1), but not in older patients. The authors noted further improvement during the course of follow-up (38% at 3 years), although it should be noted that these later evaluations were performed by unblinded investigators. A subsequent analysis by the authors suggested that baseline response to levodopa rather than patient's age best predicted a good response to transplantation (Bjorklund et al., 2003; Freed et al., 2004). FD-PET studies showed improvement in striatal FD uptake, and the authors considered the findings indicative of graft survival in 17/20 transplanted patients. Autopsy in two patients confirmed survival of TH+ neurons in each of the transplant tracks with fibers extending approximately 2-3 mms into the striatum. Cell counting noted survival of approximately 7000-40,000 cells per side. Some evidence of inflammation was observed in transplanted regions based on immunostaining for CD3 and HLA class II antigen. Neurophysiologic assessments of reaction time (RT) and movement time (MT) noted significant improvement in transplanted patients in comparison to patients in the sham group, who in contrast demonstrated significant worsening over time (Gordon et al., 2004). The procedure itself was well tolerated, however, 5 transplanted patients developed severe and disabling dyskinesias that were not alleviated by a reduction or cessation in the dose of levodopa (see discussion below).

In the second double-blind, placebo-controlled study, 34 patients were randomized to one of three treatment groups; bilateral transplantation of fetal mesencephalic tissue derived from one donor per side (11 patients), bilateral transplantation of fetal mesencephalic tissue derived from four donors per side (12 patients) or sham surgery (11 patients) (Olanow et al., 2003). Fetal mesencephalic tissue was stored for no more than 48 h in cool hibernation media and was not cultured. Solid grafts were implanted exclusively into the post-commissural putamen with deposits placed no more than 5 mm apart in an attempt to achieve continuous reinnervation of the striatum. Patients in the placebo-control group received bilateral partial burr holes which did not penetrate the inner table of the skull. All patients received cyclosporine beginning 2 weeks prior to surgery and continuing for 6 months following the operation. The primary endpoint was the change in UPDRS motor score during the practically defined off state. Transplanted patients had a significant increase in striatal FD uptake on PET (P < 0.01 compared to controls) (Fig. 6.1).

Post-mortem studies demonstrated robust graft survival with more than 100,000 TH+ cells in each striatum and extensive reinnervation of the stria-tum, similar to what we have seen in open label studies (Fig. 6.2). However, this study also failed to meet its primary endpoint (P = 0.244), although a paired comparison of the four donor versus placebo group just failed to meet significance (P = 0.096). It is noteworthy that transplanted patients in both the one and four donor groups did show improvement at 6 and 9 months (P < 0.05) and deteriorated afterwards (Fig. 6.3). Interestingly, this time period corresponds with the discontinuation of cyclosporine, raising the possibility that immune rejection might have compromised continued benefit. In support of this concept, post-mortem studies did show increased CD45 immunostaining in the region of graft deposits.

Post hoc analysis of the data in this study demonstrated that transplanted patients with milder disease in both the one and four donor groups were significantly improved in comparison to the placebo group despite the small sample size (P < 0.01). No difference between younger and older patients or in baseline response to levodopa was observed in patients who did or did not respond to transplantation. The surgical procedure was also well tolerated in this study, but a blinded and randomized review of videotapes obtained during visits conducted in the practically defined off state noted that 13/23 transplanted patients developed off-medication dyskinesia. This problem was not observed in any patient in the control group. Off-medication dyskinesias in this study were characterized by stereotypic, rhythmic, involuntary movements that predominantly affected the lower extremities and were associated with parkinsonism in other body regions. Off-medication dyskinesias thus resembled diphasic dyskinesias, and differed from classical on period levodopa-related dyskinesias which typically are more choreiform in nature and affect the head, neck, torso, and upper extremities to an equal or greater degree than the lower extremities. In this study, off-medication dyskinesias were generally mild, but were sufficiently severe in three to warrant surgical intervention.

Figure 6.1. FD-PET studies in a representative patient receiving bilateral transplantation with four donors per side (top panels) and a patient receiving a sham procedure (lower panels). Scans were obtained at baseline (left panels), 1 year (middle panels) and 2 years (right panels). Note the progressive increase in striatal FD uptake in the transplanted patient in comparison to the progressive loss of striatal FD uptake consistent with continued disease progression in the placebo treated patient (Olanow et al., 2003).

Figure 6.1. FD-PET studies in a representative patient receiving bilateral transplantation with four donors per side (top panels) and a patient receiving a sham procedure (lower panels). Scans were obtained at baseline (left panels), 1 year (middle panels) and 2 years (right panels). Note the progressive increase in striatal FD uptake in the transplanted patient in comparison to the progressive loss of striatal FD uptake consistent with continued disease progression in the placebo treated patient (Olanow et al., 2003).

Figure 6.2. TH immunostaining of striatum in patients receiving treatment with bilateral grafts using four donors per side (left panel), one donor per side (middle panel), and a sham placebo procedure (right panel). Note healthy appearing graft deposits and extensive striatal TH innervation with both four and one donors per side. Note also that grafts in the four donor group are larger and have a cylindric appearance whereas in the one donor group they are smaller, more concentric, and more densely packed (Olanow et al., 2003).

Figure 6.2. TH immunostaining of striatum in patients receiving treatment with bilateral grafts using four donors per side (left panel), one donor per side (middle panel), and a sham placebo procedure (right panel). Note healthy appearing graft deposits and extensive striatal TH innervation with both four and one donors per side. Note also that grafts in the four donor group are larger and have a cylindric appearance whereas in the one donor group they are smaller, more concentric, and more densely packed (Olanow et al., 2003).

Fetal nigral transplant study mean UPDRS motor off score by visit

Figure 6.3. Mean UPDRS scores in patients receiving bilateral transplantation with one donor per side, four donors per side, or a sham placebo procedure. Note that transplantation is associated with improvement for 6-9 months, and that transplant-related benefit disappears after approximately 9 months coincident with the cessation of cyclosporine treatment (Olanow et al., 2003).

Figure 6.3. Mean UPDRS scores in patients receiving bilateral transplantation with one donor per side, four donors per side, or a sham placebo procedure. Note that transplantation is associated with improvement for 6-9 months, and that transplant-related benefit disappears after approximately 9 months coincident with the cessation of cyclosporine treatment (Olanow et al., 2003).

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