Dopamine cell replacement in patients with Parkinson´s disease has so far been based on transplantation of dopamine neuroblasts obtained from fetal ventral mesencephalic tissue. Open-label clinical trials have given promising results, and showed that the grafted neurons can survive and function in the parkinsonian brain for many years. However, two placebo-controlled clinical trials, sponsored by the NIH and reported in 2001 and 2003, failed to reach the primary end-points, and troublesome graft-induced dyskinesias was observed in a significant number of the transplanted patients. The reasons for this variable clinical outcome, and the mechanisms underlying the dyskinetic side effect need to be clarified before any further trials can be undertaken.

Based on a careful review of the results from the previous trials a new initiative, TransEuro, has recently been funded by a FP7 program grant from the European Union. The purpose of this project is to plan and conduct a new, joint fetal cell transplantation trial, designed to address the two major issues raised by the NIH trials, i.e., the variable and overall poor clinical outcome and the development of graft-induced dyskinesias, and to pave the way for future stem cell based clinical trials.

In this talk I will discuss the rationale and strategy of this new initiative and summarize recent research aimed at clarifying three major issues: (i) the requirements that the grafted cells have to fulfil in order to be functional in the grafted striatum; (ii) the conditions of the recipient brain for the grafted cells to be optimally functional; and (iii) the mechanisms underlying the development of graft-induced dyskinesia and the role of serotonin neurons, in particular, in the induction and maintenance of this adverse effect.