Clinical application of stem cell therapy in Parkinson's disease

Abstract

Cell replacement therapies in Parkinson's disease (PD) aim to provide long-lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft-induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA-ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression.

Figure 1

Human fetal ventral mesencephalic tissue grafts provide long-lasting major relief of motor symptoms (reductions in UPDRS motor scores) and restore dopamine innervation (increases in 18F-DOPA PET uptake) in the grafted striatum in Patients 7 (A) and 15 (B) from the Lund series (modified figure from [4]). Patient 7 and Patient 15 stopped receiving any form of dopaminergic medication four and five years following operation, respectively. PET = Positron emission tomography; UPDRS = Unified Parkinson's Disease Rating Scale.

Figure 2

Schematic illustration of possible sources of stem cells for therapy in Parkinson's disease. 1) Neural stem cells (NSCs) from human fetal brain, expanded and differentiated to DA-ergic neurons; 2) Pluripotent cells generated from blastocysts (ESCs) or fibroblasts (iPSCs), expanded and differentiated to DA-ergic neurons; 3) DA-ergic neurons generated by direct conversion of fibroblasts; 4) Bone marrow-derived mesenchymal stem cells (MSCs).