Elsevier

The Lancet Neurology

Volume 10, Issue 6, June 2011, Pages 509-519
The Lancet Neurology

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Intrastriatal 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

https://doi.org/10.1016/S1474-4422(11)70097-7Get rights and content

Summary

Background

Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease.

Methods

In this randomised, double-blind study eligible patients were aged 36–70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3–4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38–70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325 000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687.

Findings

Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (−10·5 [SD 10·26] for transplantation vs −10·1 [SD 12·26] for sham surgery, p=0·9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells.

Interpretation

Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery.

Funding

Bayer HealthCare AG.

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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