Cell-based therapies for Parkinson disease—past insights and future potential

Abstract

Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route. We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.

Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation?

“…Furthermore, these improvements were only transient and highly variable among subjects (Barker et al, 2015). In addition, high morbidity and mortality were associated with this grafting procedure (Barker et al, 2015).…”

“…In addition, high morbidity and mortality were associated with this grafting procedure (Barker et al, 2015).…”

18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

“…Experimental therapies have tried to restore striatal dopamine in PD patients by gene-based and cell-based approaches. Aside from ethical considerations and logistic challenges, data concerning the use of human fetal ventral mesencephalic allografts in PD are controversial (24,25).…”

Towards stem cell based therapies for Parkinson's disease

“…The relatively focal degeneration makes it a good candidate for cell-based therapies. Since the first clinical trials using fetal midbrain tissue to replace the DA neurons lost in the disease were initiated in the late 1980s, hundreds of patients have been grafted with fetal tissue worldwide, and a number of them have shown long-term graft survival with good clinical outcome, coupled to physiological release of dopamine over decades (reviewed by Barker et al, 2015). With the derivation of human embryonic stem cells (hESCs) (Thomson et al, 1998), a new scalable cell source that could potentially replace fetal tissue became available (Fig.…”