Fast track — ArticlesIntrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial
Introduction
The cardinal motor features of Parkinson's disease (PD) primarily result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, which leads to severe depletion of dopamine in the striatum.1, 2 Levodopa, a precursor of dopamine, continues to be the most widely used and efficacious treatment for controlling the symptoms of PD,3 but long-term oral treatment is associated with involuntary movements (dyskinesia) and motor fluctuations in most patients.4 These complications are thought to be related to a diminished buffering capacity and wide variation in dopamine levels owing to nigrostriatal degeneration, which leads to pulsatile stimulation of dopamine receptors.3, 5
Research has become focused on long-term, continuous dopamine replacement in the striatum by dopaminergic cell transplantation to avoid or lessen the motor complications associated with chronic intermittent levodopa therapy.6, 7, 8, 9 Levodopa is released by human retinal pigment epithelial (RPE) cells as an intermediate product in the melanin biosynthetic pathway.10, 11, 12 Thus, transplantation of these cells into the striatum might improve continuity of levodopa administration compared with that achieved with oral levodopa preparations. A novel, cell-based product, in which human RPE cells are bound to a microcarrier support matrix, has been developed. In animal models of PD, transplantation of these bound cells lessened the severity of motor symptoms, decreased the rate of binding of 14C-raclopride, and was well tolerated.13, 14
On the basis of these results, an open-label exploratory study was done to assess the safety and tolerability of unilateral transplantation of microcarrier-bound RPE cells into the striatum in six patients with advanced PD.15, 16, 17, 18 The implants were well tolerated and no major safety issues were noted, including no evidence of dyskinesia while off all anti-PD medication for at least 12 h (off state), which has been seen with other cell-based therapies.19 The unified Parkinson's disease rating scale (UPDRS) part 3 (motor) off-state scores were improved at months 6, 12, 24, and 48 by 33%, 48%, 41%, and 48%, respectively.16, 17, 18 In view of these results we further assessed the safety, tolerability, and efficacy of microcarrier-bound RPE cells.
Section snippets
Patients
We enrolled patients into a phase 2, multicentre, randomised, double-blind study with a sham surgery control. All procedures were approved by the local institutional review boards in each investigational centre. Patients who were already attending or were referred to neurology centres involved in the study were recruited from September, 2002, to March, 2007. All patients were required to provide written informed consent. Inclusion and exclusion criteria are listed in panel 1. Patients underwent
Results
157 patients with advanced PD were screened for inclusion in the study at 12 participating clinical centres, of whom 76 were enrolled and underwent randomisation. The age distribution of patients is shown in webappendix p 1. Five patients were not treated: one withdrew consent, one did not meet the inclusion and exclusion criteria, and one had an adverse event; reasons were not provided for two. The remaining cohort of 71 patients underwent surgery and comprised the modified full analysis set (
Discussion
In this phase 2 study, transplantation of carrier-bound human RPE cells showed no treatment effect compared with sham surgery in patients who had advanced PD. Thus, the primary efficacy endpoint was not met. Additionally, no significant differences were seen between groups for the secondary outcomes. Of note is that the improvement in the UPDRS off-state motor scores in both study groups was seen at the 12-month assessment (figure 3).
Overall, the reduction in the UPDRS off-state motor scores
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