Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen


Expert Rev Neurother. 2011;11(9):1325-1339. 

In This Article

Cell Replacement Therapy & PD: Milestones

Parkinson's disease is primarily characterized by a selective loss of a small population of a specific subset of neurons (A9 DA neurons), making it attractive to study the effect of direct replacement of new and healthy A9 DA neurons. Since the concept of CRT emerged as a successful therapeutic alternative in PD, many obstacles have restricted the direct translation to the clinic, making it more complex than was initially expected. The complexity of the experimental design in CRT, among others, still resides on which cells are best suited to provide functional A9 DA neurons and where to transplant them in order to re-establish the affected system.

In the mid-1970s, work carried out by several groups led by Olson, Seiger and Hoffer,[7–10] as well as Björklund and Stenevi,[11–13] initiated the concept of cell replacement in PD. The basic concept was to provide dopamine, through transplantation of dopamine secreting cells, in the caudate and putamen of the striatum. The striatal target was selected to ensure the prompt release of DA in the primary area affected by DA nigral cell loss. These works provided extensive evidence that grafted DA cells isolated from the ventral mesencephalon (VM) retained the capacity for long-term survival in the degenerated brain, reinnervate striatal targets and significantly improve motor functions.[14] Nigral transplantation was also tested, as this could be a more physiological approach. Although the cells survived in the nigra, they failed to properly extend axons through the nigrostriatal pathway and innervate the striatum, thus no functional recovery was documented.[14–21] As fetal tissue availability is limited and may present ethical implications, researchers searched for alternative sources of DA-secreting cells. Pioneering works, such as those made by Freed et al.,[22] Backlund et al.[23] and Madrazo et al.,[24] strengthened the potential of CRT for PD, using autologous grafts of the adrenal medullary tissue. Graft survival was observed in transplanted rats[22] and in MPTP-treated monkeys, and some symptomatic improvements but limited cell survival after transplantation, were demonstrated.[25,26] In 1987, the first clinical use of adrenal medullary graft was reported with significant improvements; however, later on, trials demonstrated less favorable outcomes.[24,27] Several longitudinal studies have analyzed over 300 PD patients grafted with tissue from different origins and showed that most of the patients with a positive clinical outcome during the off-drug period presented improved motor symptoms by 30–60%, as measured by the United Parkinson's Disease Rating Scale (UPDRS).[28] Moreover, formed DA neurons from the transplanted tissue reinnervated the denervated striatum and became functionally integrated, restoring striatal dopamine release and giving rise to symptomatic relief. Implanted cells were detected 10 years after transplantation in the brain of treated patients.[29] However, two double-blind placebo-controlled studies using embryonic mesencephalic tissue transplantation in PD patients demonstrated disappointing results. There are several possible explanations for these results, but it clearly proved the need to develop other sources of DA neurons, and refine both the transplantation techniques and suitable patient selection. Owing to the limited availability of embryonic tissue, the possible ethical implications and the high variability of functional outcome after transplantation, future CRT in PD needs to rely on alternative tissue sources in which self-renewable stem cells could be propagated indefinitely and in a standardized manner. In this way, many alternatives were explored to generate homogeneous DA neurons, using among others, embryonic stem cells (ESCs),[30] neural stem cells (NSCs),[31] induced pluripotent stem cells (IPSs)[32] and adult multipotent stem cells, primarily represented by mesenchymal stem cells (MSCs), such as bone marrow stromal cells.[33] It has been demonstrated that cells with DA properties can be generated from different sources of stem cells and improvements can be seen after implantation of these cells in animal models of PD.[34–39] The accumulated evidence to date, make it difficult to expect a complete recovery of CRT-treated PD patients. Data obtained from animal studies demonstrated that the maximal recovery achieved was approximately 50–60%. This could be related to the implantation site in the striatum, consequently not fully restoring the nigrostriatal pathway. This could also suggest that dopamine may not be the only player needed to restore the affected system in PD. Regarding the implantation site, most of the grafts have been placed in the striatum, which is not the natural site of the DA neurons. Theoretically and according to the residence site of DA neurons, they should be transplanted into the substantia nigra pars compacta area. This procedure carries other major problems as mentioned above, including increased surgical risk and the need for growth of DA neuron projections through the nigrostriatal pathway, which has not yet been effectively achieved.

Currently, two clinical trials involving CRT and PD are recruiting patients, according to the US NIH.[201] These trials are now in Phase I and III and include autologous transplantation into the striatum of bone marrow MSCs[202] and embryonic DA mesencephalic cells,[203] respectively. In addition, a clinical trial on IPS generation from somatic cells of PD patients has been recently initiated.[204]