TRANSEURO Open Label Transplant Study in Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional

Summary: 
      The Transeuro Transplant study is a trial which will involve grafting foetal tissue into the
      brain of patients with Parkinson's disease, who are already been followed in the
      observational study. The tissue inserted in the brain is to help replace and rebuild lost
      dopamine from the brain due to Parkinson's disease.

      Update April 2019:

      A total of 11 PD patients were grafted in Cambridge, UK and Lund, Sweden. No further
      surgeries are planned. The final patient will complete the study's clinical endpoint (36
      months post-graft) in 2021. We continue to assess these patients bi-annually alongside a
      control group which did not receive any intervention.
    

Detailed description: 
      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.
    

Intervention name(s): Transplant
Intervention type(s): Procedure
Intervention description(s): Bilateral Neural Allo-Transplantation with Fetal Ventral Mesencephalic Tissue
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Parkinson's Disease; Allo-Transplantation; Fetal Ventral Mesencephalic Tissue