Degenerative Neurological and Neuromuscular Disease Stem cells and regenerative therapies for Parkinson ’ s disease

Correspondence: Roger Barker Cambridge Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK Tel +44 1223 331160 Fax +44 1223 331174 Email rab46@cam.ac. uk Abstract: Currently the mainstay of Parkinson’s disease (PD) therapy is the pharmacological replacement of the loss of the dopaminergic nigrostriatal pathway using drugs such as dopamine agonists and levodopa. Whilst these drugs effectively ameliorate some of the motor features of PD, they do not improve many of the nonmotor features that arise secondary to pathology outside of this system, nor do they slow the progressive neurodegeneration that is a characteristic of the disease. Regenerative therapies for PD seek to fill this therapeutic gap, with cell transplantation being the most explored approach to date. A number of different cell sources have been used in this therapeutic approach, but to date, the most successful has been the use of fetal ventral mesencephalic (VM) tissue that contains within it the developing nigral dopaminergic cells. Cell transplantation for PD was pioneered in the 1980–1990s, with several successful open-label trials of fetal VM transplantation in patients with relatively advanced PD. Whilst these findings were not replicated in two subsequent double-blind sham-surgery controlled trials, there were reasons to explain this outside of the one drawn at the time that these therapies are ineffective. Indeed all these studies have provided evidence that following the transplantation of fetal VM tissue, dopaminergic cells can survive long term, produce dopamine, and bring about clinical improvements in younger patients over many years. The use of fetal tissue, irrespective of its true efficacy, will never become a widely available therapy for PD for a host of practical and ethical reasons, and thus much work has been put in recently to exploring the utility of stem cells as a source of nigral dopaminergic neurons. In this respect, the advent of embryonic stem cell and induced pluripotent cells has heralded a new era in cell therapy for PD, and several groups have now demonstrated that these cells can form dopaminergic neurons which improve functional deficits in animal models of PD. Whilst encouraging, problems with respect to the immunogenicity and tumorigenicity of these cells means that they will need to be used in the clinic cautiously. Other regenerative therapies in PD have been tried over the years and include the use of trophic factors. This has primarily involved glial cell line-derived neurotrophic factor (GDNF) and again has produced mixed clinical effects, and in order to try and resolve this, a new trial of intraputamenal GDNF is now being planned. In addition, a new trial for platelet derived growth factor as a treatment for PD has just completed recruitment, and PYM50028 (Cogane) an oral agent shown in animal models to reduce the effects of MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) lesioning by the induction of growth factors is currently under investigation in a multicentre Phase II trial. Overall, there are a number of promising new regenerative therapies being developed and tested in PD, although the true long-term efficacy of any of these in large numbers of patients is still not known.