TRANSEURO Open Label Transplant Study in Parkinson's Disease

Clinical trials of cell therapy in PD patients were first performed in Lund in the late 1980s, followed by a number of similar, small trials in other European and North American centres. These initial studies performed on small groups of advanced PD patients were all open label but firmly established safety of the procedure. The results obtained in these trials have shown that the grafted dopaminergic [DA] neurons can survive and function long-term, over more than 10 years, and that some patients have shown clear clinical benefits, especially with respect to their bradykinesia and rigidity, with reductions in L-dopa requirements. Using functional imaging it has also been shown that the grafted DA neurons can restore striatal DA release and provide a sustained re-activation of motor cortical areas, i.e. key areas that were underactive prior to grafting.

Post-mortem studies have shown excellent long-term survival of the grafted DA neurons, notwithstanding the observation that some of the long-term surviving transplants (at 12-15 years after grafting) have now been shown to contain signs of PD-related pathologies, i.e. neuronal Lewy-bodies and alpha-synuclein positive inclusions in the grafts. However, such changes have been observed only in some and not in all patients and when seen the extent of the pathology is limited to a small number of the grafted DA cells and the clinical consequence, if any, not known.

However, the outcomes of two NIH sponsored double blind placebo controlled trials, which published their main findings in 2001 and 2003, have raised major concerns. In both these trials the grafted patients did not show any significant improvement overall compared to sham-operated controls at 1 and 2 years post grafting. Furthermore, a significant number of patients in both trials developed GIDs, which in some cases were so severe that further neurosurgery was needed to remedy the situation.

The reasons for the variable, and overall poor, outcome in these trials, including the generation of GIDs, have been the subject of much debate but have recently centred on three key elements, with an additional possible fourth element:

• The selection of patients in terms of clinical phenotype, disease stage and pattern of striatal dopaminergic denervation at the time of grafting;
• The differences in immunosuppressive regimes and the risk that incomplete immunosuppression in combination with the use of solid graft methods may lead to the development of detrimental immune/inflammatory reactions at the graft site with compromise of the grafted dopamine cell function;
• The mode of engraftment and differences in graft cell survival, and the risk for inhomogeneous delivery of dopaminergic neurons and the generation of potentially dyskinesia-inducing "patchy" innervations in the host striatum;
• A final possible element is the composition of the grafted tissue and the ratio of serotoninergic to dopaminergic neurons within the graft. There is emerging evidence that serotoninergic neurons can release dopamine in a relatively unregulated fashion given they lack transporters for it, and as such may use L-dopa as a false transmitter which may not only underlie the development of L-dopa induced dyskinesia's but may also contribute to GIDs.

Failure of the NIH trials to demonstrate any overall clinical benefits in the grafted patients, and the unexpected and worrisome development of GIDs in a significant number of patients in these trials has represented a major hurdle for the future development of cell based therapies for PD and it is in this and related areas that this project seeks to move the field forward and go beyond the current state of the art for this treatment approach.

This project has gathered together all the available expertise in this area to resolve or reduce the risk of the previous complications seen with VM transplants in patients with PD. We will conduct a new round of clinical trials, involving a step-by-step optimisation of all technical aspects of the grafting procedure and patient selection and assessment, in order to improve clinical efficiency and consistency, in the absence of troublesome dyskinesia's.