The TransEuro open-label trial of human fetal ventral mesencephalic transplantation in patients with moderate Parkinson's disease

Abstract

Transplantation of human fetal ventral mesencephalic tissue in individuals with Parkinson's disease has yielded clinical benefits but also side effects, such as graft-induced dyskinesias. The open-label TransEuro trial ( NCT01898390 ) was designed to determine whether this approach could be further developed into a clinically useful treatment. Owing to poor availability of human fetal ventral mesencephalic tissue, only 11 individuals were grafted at two centers using the same tissue preparation protocol but different implantation devices. No overall clinical effect was seen for the primary endpoint 3 years after grafting. No major graft-induced dyskinesias were seen, but we observed differences in outcome related to transplant device and/or site. Mean dopamine uptake improved at 18 months in seven individuals according to [¹⁸F]fluorodopa positron emission tomography imaging but was restored to near-normal levels in only one individual. Our findings highlight the need for a stem cell source of dopamine neurons for potential Parkinson's disease cell therapy and provide critical insights into how such clinical studies should be approached.

Fig. 1. Change in UPDRS Part III in the defined OFF period.

a, Individual trajectories. Time since entering the study was mean centered for the control individuals to align the x axes with the transplanted group. b,c, Average change per month by group (b) and device used (c). The green arrow indicates patient 79, and the brown arrow corresponds to patient 60 with near normalization on their dopamine PET scans.

Fig. 2. Analyses for dopaminergic PET imaging.

Results of mixed two-way analyses of covariance (ANCOVAs) for bilateral putamen [¹⁸F]FDOPA K_i (a; P = 0.066) and [¹¹C]PE2I BP_ND (d; P = 0.000062) including group (transplant: n = 8; control: n = 16) and visit (before transplant (Pre-Tx)/baseline and after transplant (Post-Tx)/18-month follow-up (18m FU) for transplant/control groups, respectively) as independent variables, adjusting for mean-centered age at baseline. Results of two-way repeated measures ANCOVAs within the transplant group (n = 8) are also shown for [¹⁸F]FDOPA K_i (b; P = 0.025) and [¹¹C]PE2I BP_ND (e; P = 0.000057). Strip plots illustrate two-way interactions between region (bilateral putamen and caudate) and visit (baseline, before transplant and after transplant), adjusting for mean-centered age and disease duration at baseline. Bootstrapped means and 95% confidence intervals (bias-corrected and accelerated procedure, 10,000 replicates) by surgical device (TRN3/TRN4/R–L/control) and visit (before transplant/baseline and after transplant/18-month follow-up for transplant/control, respectively) were generated considering data from all putamen unilaterally and plotted for both [¹⁸F]FDOPA K_i (c; device n = 5 (TRN3), 8 (TRN4), 6 (R–L), and 32 (control)) and [¹¹C]PE2I BP_ND (f; device n = 4 (TRN3), 6 (TRN4), 6 (R–L) and 32 (control)). Partially transparent lines represent data from individuals, whereas opaque lines and error bars represent estimated marginal means and 95% confidence intervals, respectively. Dotted horizontal lines for putamenal [¹⁸F]FDOPA K_i (a–c) represent the lower bound (pooled mean – 2 s.d.) for a healthy older cohort (n = 6 studies; total n = 71). Significance was analyzed by Tukey-adjusted post hoc tests; *P < 0.05; **P < 0.01; ***P < 0.001 (two sided); Ct, control; MA, most affected side; LA, least affected side.

Fig. 3. Analyses for 5-HT [¹¹C]DASB PET imaging.

a, Results of the mixed two-way ANCOVA for the bilateral putamen including group (n = 8 (transplant) and 14 (control)) and visit (before transplant/baseline and after transplant/18-month follow-up for transplant/control groups, respectively) as independent variables (P = 0.031). b, Within the transplant group (n = 8), a two-way repeated measures ANCOVA revealed an interaction between region (bilateral putamen and caudate) and visit (baseline, before transplant and after transplant; P = 0.038). Both analyses were adjusted for mean-centered age and disease duration at baseline. Partially transparent lines represent data from individuals, whereas opaque lines and error bars represent estimated marginal means and 95% confidence intervals, respectively. Significance was assessed by Tukey-adjusted post hoc tests; *P < 0.05, **P < 0.01 and ***P < 0.001 (two sided).

Fig. 4. Dopaminergic PET after hfVM transplantation.

Representative [¹⁸F]FDOPA (left) and [¹¹C]PE2I (right) parametric images for two bilaterally transplanted patients whose postoperative levels of dopamine synthesis and transporter expression were either high (patient 60) or comparatively modest (patient 54). Dopaminergic PET data are overlaid onto patient T1-weighted magnetization prepared rapid gradient echo (MPRAGE) scans rigidly aligned to the Montreal Neurological Institute (MNI) template and displayed as axial slices covering the putamen; R, right; L, left.