Cell therapy in Parkinson's disease

Abstract

The clinical studies with intrastriatal transplants of fetal mesencephalic tissue in Parkinson's disease (PD) patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. However, there are currently several problems linked to the use of fetal tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients, 2) variability of functional outcome with some patients showing major improvement and others modest if any clinical benefit, and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in PD. For the development of a clinically useful cell therapy, we need to define better criteria for patient selection and how graft placement should be optimized in each patient. We also need to explore in more detail the importance for functional outcome of the dissection and cellular composition of the graft tissue as well as of immunological mechanisms. Strategies to prevent the development of dyskinesias after grafting have to be developed. Finally, we need to generate large numbers of viable DA neurons in preparations that are standardized and quality controlled. The stem cell technology may provide a virtually unlimited source of DA neurons, but several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.

FIG. 1.

Data compiled from 14 of the PD patients operated in Lund, showing the change in UPDRS motor score in individual patients at 2 years after transplantation (expressed as percentage relative to the preoperative value; left panel), and the increase in FD-PET uptake in the putamen at this postoperative time point (right panel). The FD-PET values are expressed both as the increase in percentage of preoperative value (values shown at left), or as the absolute value expressed as percentage of normal age-matched controls.

FIG. 2.

Time course of symptomatic improvement in the patients reported in the Olanow et al. study (left panel) and the Freed et al. study (right panel), compared with the changes observed in two groups of PD patients transplanted in Lund., The magnitude of symptomatic improvement seen over the first 4-6 months in the two placebo-controlled studies matches fairly well the improvement seen in the Lund patients over this time period. However, whereas the Lund patients continued to improve over the subsequent 12-18 months, the patients in the Olanow and Freed studies did not. As discussed in the text, this difference may be readily explained by the differences in immunosuppressive treatments used: in the Olanow et al. trial, the immunosuppression was limited to cyclosporine only for the first 6 months, and no immunosuppression at all was used in the Freed at al. trial. The Lund patients were given triple immunosuppressive regimen for at least 12 months.

FIG. 3.

Time course of the host immune response to intrastriatal allogeneic grafts, as seen in experiments in nonimmunosuppressed rats. The initial immune response subsides over the first 5-8 weeks but shows a gradual, variable reappearance at 12-18 weeks after grafting. This delayed immune/inflammatory response is observed as a variable activation of host microglia. In immune-activated grafts, there is an increased number of activated microglia, as well as an increased number of major histocompatibility complex class I- and class II-expressing cells (not shown). DA neuron survival is compromised in such immune-activated transplants. Data compiled from Shinoda et al.,