Abstract
Parkinson's disease (PD) is a common debilitating neurodegenerative disease. The motor symptoms of PD are caused mainly by a progressive loss of dopaminergic neurons from the substania nigra, resulting in a loss of dopamine production. Current therapies are palliative and, in the long term, ineffective. In addition, some can result in significant clinical side effects. The relatively localized pathology of PD makes it an ideal candidate for cell replacement therapy. Initial efforts focused on fetal cell transplantation, and significant clinical benefit lasting more than 10 years has been reported in some cases. However, the approach is controversial and results have been inconsistent. Inherent limitations of this approach for widespread use are the limited availability and variability of transplant material. In contrast, the self-renewal and differentiation potential of human pluripotent stem cells (hPSCs) make them a promising alternative cell source for cell replacement therapy for PD. Efforts in the past decade have demonstrated that hPSCs can be induced to differentiate in culture to functional dopaminergic neurons. Studies in delivering these cells into PD animal models have demonstrated survival, engraftment, and behavioral deficit improvements. Several groups are developing these cells with clinical trials in mind. Here, we review the state of the technology and consider the suitability of current manufacturing processes, cell purity, and tumorgenicity for clinical testing.
Highlights
Parkinson’s disease (PD) is a common debilitating neurodegenerative disease
Methods of generating dopaminergic neurons During the past decade, there has been an explosion in developing methods to direct DA neuronal differentiation of human embryonic stem cell (hESC), and many groups have reported the generation of tyrosine hydroxylase (TH)-positive DA neurons from hESCs [21,22,27,28,29,30,31,32]
A number of groups have made considerable progress in demonstrating that authentic A9 DA neurons can be produced in vitro with high efficiency from hESC and induced pluripotent stem cell (iPSC) lines, including lines derived from patients with PD
Summary
Parkinson’s disease (PD) is a common debilitating neurodegenerative disease. The motor symptoms of PD are caused mainly by a progressive loss of dopaminergic neurons from the substania nigra, resulting in a loss of dopamine production. Evidence supporting the rationale for developing an hPSC-derived DA cell replacement therapy is provided by animal studies that since the early 1980s have evaluated the effects of transplantation of fetal mesencephalic tissue containing nigral DA cells into the striatum of rodents and non-human primates [4,5,6,7,8,9] The majority of these experimental studies demonstrated that this approach is capable of reversing behavioral parkinsonism despite minimal survival and integration of engrafted cells in the host brain, providing the basis for subsequent clinical trials in which fetal mesencephalic tissue was transplanted in patients with PD [10,11,12,13]. Whether this is a reaction to the surrounding pathological tissue or the transmission of an adventitious agent from the host remains unclear (reviewed by Braak and Del Tredici [17] in 2008)
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