Chapter 14 - Neural grafting in Parkinson’s disease: Problems and possibilities

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Abstract

Neural transplantation has emerged as a possible therapy for Parkinson’s disease (PD). Clinical studies performed during the 1990s, where dopaminergic neurons derived from the human embryonic brain were transplanted into striatum of patients with PD, provided proof-of-principle that long-lasting therapeutic benefits can be achieved. Subsequent studies, in particular two that followed a double-blind, sham surgery, placebo-control design, showed variable and mostly negative results. They also revealed that some patients develop involuntary movements, so called graft-induced dyskinesias, as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement before it can successfully be performed in a large series of patients. In this review, we describe the clinical neural transplantation trials in PD and the likely importance of factors such as patient selection, trial design, preparation of the donor tissue, and surgical techniques for successful outcome and avoiding unwanted side effects. We also highlight that it was recently found that neuropathological signs typical for PD can appear inside some of the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD.

Introduction

Over the past 30 years, neural transplantation has emerged as a possible therapy for Parkinson’s disease (PD). Today we know that grafted neural cells can survive for over 20 years and exert beneficial effects in PD patients. Results obtained during the 1990s in open-label trials with grafted dopaminergic neurons derived from the human embryonic brain were very encouraging. The patients displayed impressive improvements of symptoms and restoration of dopaminergic neurotransmission. By contrast, two double-blind, sham surgery, placebo-controlled trials with nigral transplants in PD reported no improvement in grafted groups on primary endpoints. These trials also highlighted that some patients develop involuntary movements, so called graft-induced dyskinesias (GIDs), as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement and is difficult to successfully perform in a large series of patients.

The aims of this review are to briefly review clinical neural transplantation trials in PD and describe factors that may influence likelihood of a successful outcome, such as patient selection, transplantation technique, and trial design. We underscore the problem of GIDs and how they might be avoided in the future. We describe other practical obstacles linked to fetal tissue transplantation that currently prevent transfer of the technology into an established treatment, and how they might be circumvented in a forthcoming multicenter trial that is sponsored by the European Commission. We highlight recent findings that neuropathological features typical for PD appear inside the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD.

Section snippets

Open-label transplantation trials in PD

Clinical trials using fetal ventral mesencephalic (VM) tissue began in the late 1980s in Mexico (Madrazo et al., 1988) and Sweden (Lindvall et al., 1989) with tissue from 12–14–week- and 6–8-week-old fetuses/embryos, respectively. The tissue was transplanted into the striatum with minimal clinical improvement, at least in the patients from Sweden. However, by refining the techniques, several subsequent open-label clinical studies demonstrated that the patients can display significant

Double-blind placebo-controlled transplantation trials in PD

As the 1990s progressed, more data emerged from a number of open-label VM transplant studies in PD showing that these transplants were effective at treating advanced PD in some cases, although the emerging use of DBS caused some to question whether this was a better, more practical, solution in the management of advanced motor PD. However, with a change in administration in the US and with encouragement from the initial open-label results, two double-blind placebo-controlled trials of fetal VM

How does one reconcile differences in outcomes of open-label and double-blind trials?

There are a number of possible interpretations. Firstly, one could take a very dogmatic approach, concluding that open-label studies are subject to patient and assessor bias with placebo effect and thus the double-blind studies reveal the true answer—namely neural grafting does “not” really work in PD.

Secondly, one could take the opposite view and say that the double-blind studies were inadequately powered to see any benefit. Thus, they might be subject to Type II errors, namely the studies are

Neuropathological changes in grafts raise new concerns

As discussed above, the safety and efficacy of VM grafting for PD have become major points of discussion, but another important observation has further complicated the future of neural grafting in PD. This is the demonstration in post-mortem studies that neurons in fetal VM transplants contain alpha-synuclein pathology (Kordower et al., 2008a, Kordower et al., 2008b, Li et al., 2008b, Li et al., 2010). This suggests that the grafts might ultimately undergo the fate of the patients’ own

Cell transplantation in PD—where do we go from here?

Evidently, cell-based therapies for PD using fetal VM have had a chequered history—showing in some cases significant long-lasting benefits, whilst in other patients troublesome side effects have arisen. As described above, there is now accumulating data to suggest that some of the critical factors in the success (or failure) of these fetal VM transplants for patients with PD have been identified and that the field is ready to move forward again (although not all would agree—see Olanow et al.,

Safety and regulatory issues for clinical application of stem cells in the brain

Transplantation of neurons derived from a highly proliferative population of stem cells into the brain involves potential safety risks, which we have reviewed extensively elsewhere (Li et al., 2008a), mainly associated with the possible inclusion of proliferating cells that can form tumors. In any stem cell-based transplantation therapy, regardless of the target organ or tissue, tumor growth is a major safety concern. For stem cell therapy in the brain, it is a particularly grave concern. The

Future perspectives and concluding remarks

Cell transplantation still remains a very promising therapeutic approach for PD. While the initial promise and excitement of the early open-label trials with fetal VM grafts in PD has been diminished and undermined by the subsequent placebo-controlled, double-blind trials, we believe that the past 5–10 years has seen several developments that now make it possible once again to perform successful trials using fetal VM tissue in select groups of PD patients. By refining both the transplantation

Acknowledgements

All authors are part of the Collaborative Project TRANSEURO funded by the European Commission under the Seventh Framework Programme—HEALTH 2009—(Contract no. 242003). PB is sponsored by the Swedish Parkinson Foundation and the Swedish Brain Foundation. PB and MP are part of the Linnéaus research environment BAGADILICO, sponsored by the Swedish Research Council. PB and MP are funded by the Swedish Research Council. RAB is supported by grants from the PDS (UK), the Cure-PD Trust, and an NIHR

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