Pluripotent Stem Cell Therapies for Parkinson Disease: Present Challenges and Future Opportunities

Abstract

In Parkinson's disease (PD), there are currently no effective therapies to prevent or slow down disease progression. Cell replacement therapy using human pluripotent stem cell (hPSC)-derived dopamine neurons holds considerable promise. It presents a novel, regenerative strategy, building on the extensive history of fetal tissue grafts and capturing the potential of hPSCs to serve as a scalable and standardized cell source. Progress in establishing protocols for the direct differentiation to midbrain dopamine (mDA) neurons from hPSC have catalyzed the development of cell-based therapies for PD. Consequently, several groups have derived clinical-grade mDA neuron precursors under clinical good manufacture practice condition, which are progressing toward clinical testing in PD patients. Here we will review the current status of the field, discuss the remaining key challenges, and highlight future areas for further improvements of hPSC-based technologies in the clinical translation to PD.

Keywords: Parkinson’s disease; directed differentiation; dopamine neuron; midbrain development; neural transplantation; pluripotent stem cells; regenerative medicine.

FIGURE 1

Comparison of published differentiation protocols for dopamine neuron derivation from human pluripotent stem cells. While all protocols use comparable strategies for neural induction (dual-SMAD inhibition) and for midbrain floor plate induction (activation of SHH pathway and WNT pathway), there are differences in the use of FGF8 (highlighted in pink) and the timing and concentration of the WNT activating compounds (typically CHIR99021; highlighted in yellow).