Drug discovery toward successful cell transplantation therapy for Parkinson's disease using human pluripotent stem cells

Abstract

Cell transplantation therapy using human pluripotent stem cell (PSC)–derived midbrain dopaminergic (mDA) neurons is soon expected to be available for patients with Parkinson's disease (PD). Highly efficient and reproducible protocols for the induction of mDA neurons for clinical application have already been reported, and the therapeutic potential and safety of these cells have been studied in parkinsonian animal models as preclinical trials. However, a new strategy that improves the survival and functional quality of the grafted mDA neurons is needed to achieve maximal efficacy of the cell transplantation therapy. One strategy would definitively be to adapt the brain's microenvironment with the use of small compounds, such as soluble factors and clinical drugs, in addition to current pharmacotherapies for PD. In this mini review, we focus on recent findings regarding the induction of mDA neurons from human PSCs toward clinical application and on a complementary strategy of drug treatment toward more efficient cell transplantation therapy for PD patients. In context Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by the selective degeneration of midbrain dopaminergic (mDA) neurons. The loss of mDA neurons causes resting tremor, rigidity, bradykinesia, gait disturbances, and postural instability. Earlier, the main treatment for PD was pharmacotherapy using levodopa and dopamine receptor agonists. The efficacy of pharmacotherapy is gradually lost during long-term treatment, however, and side effects, such as the on–off phenomenon, wearing-off phenomenon, and drug-induced dyskinesia, begin to appear in later stages. In addition, pharmacotherapy cannot recover the lost mDA neurons. Therefore, cell transplantation therapy, which originally used aborted human embryonic tissue but has now expanded to other pluripotent stem cells (PSCs) sources, was developed to restore the lost mDA neurons in PD patients as a therapeutic option. In this study, we review recent progress in cell transplantation therapies and examine how drug treatment can improve PD patient outcome.