Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease.
Stover NP, Bakay RAE, Subramanian T. et al.;
Commented by , 20 Feb 2006
Background
Dopaminergic cell transplantation in patients with PD had fallen in disfavour after disappointing results and uncontrollable dyskinesias were reported in patients with transplantation of fetal dopaminergic cells. It remained open if transplantation of other type of cells may provide better results.
Human retinal pigment epithelial cells produce levodopa, are found in the inner layer of the retina, they can be isolated form postmortem human eyes, grown easily in culture and survive when attacked to gelatin microcarriers. Their transplantation into striatum has been shown to be effective in animal models of PD (ref. 1 ).
Objectives
The objective of this study was to evaluate the safety and efficacy of unilateral implantation of human retinal pigment epithelial (RPE) cells attached to gelatin microcarriers into the putamen contralateral to the more symptomatic side of patients with PD.
Methods
This was a small, open-label pilot study in a single center. Six patients with advanced PD underwent stereotactic surgery with intrastriatal implantation of approximately 325.000 RPE cells on microcarriers.
The main outcome measure was change from baseline to 12 months in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscore with the patients in the practically defined off state, i.e. not taking antiparkinsonain medications for at least 12 hours over night. Secondary measures included UPDRS-total, UPDRS-ADL, Dyskinesia Rating Scale and PDQ-39. No immunosupression was used.
Results
All patients tolerated the implants well. At 12 months after the implantation there was an average improvement of 48% (range 41-61%; p=0.03) in the UPDRS motor subscore in the off state. This improvement was sustained through 24 months (average 41%, range 29&-58%; p=0.03).
Improvements were also seen in UPDRS total score, activities of daily living, motor fluctuations (increased "on" time, decreased "off" time) and quality of life (PDQ-39 score). No off-state dyskinesias were observed.
Professor Emre's comments
The history of dopaminergic cell transplantation in PD is characterized by ups and downs, excitements and disappointments. The euphoria triggered by dramatic improvements described by a mexican group in late 1980s, using human adrenal auto-grafts, was soon replaced by a sobering disappointment.
The hope that less mature cells with a higher potential for better functional integration was first fuelled with promising results from open label studies in small number of patients; the results of the larger, randomized, double-blind, sham-surgery controlled trial, however, inflicted a renewed blow against this strategy: there were no significant benefits and approximately 1/3 of patients developed uncontrollable off-state dyskinesias (ref. 2, ref. 3 ).
PET studies and autopsy findings from a deceased patient revealed that the problem was not graft rejection or cell survival, the cells did survive and seemed to make functional connections.
These results were perceived by many as an epitaph to cell transplantation approach in the treatment of PD. The results of this small study imply that his may not need to be the case. Especially important is the lack of off-state dyskinesias despite substantial improvement in motor function.
It may not be obvious in the first glance why cultured retinal epithelial cells may be any different than other sources of dopaminergic cells such as those from fetal nigral transplants. Human RPE cells do not appear to make any synaptic connections, since they are non-neuronal cells and are attached to microcarriers; they simply supply levodopa.
Could it be that a simple source of continuous intrastrital levodopa supply is better than cells making synaptic connections? This may be so, but before this method is praised prematurely, results from larger controlled studies must be awaited, as the history of cell transplantation in PD has been full of false hopes and grave disappointments.
References:
1. Watts RL, Raiser CD, Stover NP, et al. Stereotaxic intrastriatal implentation of human retinal pigment epithelial cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson’s disease. Journal of Neural Transmission Supplement 2003; 65; 215-227
2. Freed CR, Grene PE, Beze RE, et al. Transplantation of embryonic dopamine nerones fors evre Parkinson’s disease. New England Journal of Medicine 2001; 344 (10); 710-719
3. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Annals of Neurology 2003; 54 (3); 403-414