Retinoic acid-based technologies for cell replacement therapy of Parkinson’s disease

Stem cell-based cell replacement therapies have strong potential to provide a restorative treatment for Parkinson’s disease (PD), affecting ~10 million people worldwide and prevalence steadily increasing.

We have developed novel technologies to produce midbrain dopamine (mDA) neurons from human pluripotent stem cells (hPSCs), that principally differ from current state-of-the-art protocols by utilizing retinoic acid (RA), instead of the GSK3β inhibitor CHIR99021, to impose midbrain (MB) identity to hPSC-derived neural progenitors.

RA-based differentiation promotes rapid suppression of pluripotency and results in robust specification of mDA neurons, with low batch-to-batch and cell line-to-cell line variability.

When grafted into parkinsonian rats, RA-specified preparations generate mDA neuron-rich graft and restore motor deficits.

In this proposal, we intend to validate and optimize in vivo-performance of RA-specified preparations in parkinsonian rodents.

We have also developed tools to sub-pattern mDA neuron-precursors into different rostro-caudal and mediolateral identities, and we will explore to what extent this will influence graft outcome, functional efficacy and composition of mDA neuron subtypes in grafts after transplantation.

We believe that RA-based vMB specification provide a novel and attractive route towards a cell therapy for PD that can be explored for clinical translation after preclinical evaluation in animal models of PD.