Strategies for bringing stem cell-derived dopamine neurons to the clinic-The NYSTEM trial.

Over the last 10 years, there has been significant progress in defining culture conditions to derive bona fide human midbrain dopamine (mDA) neurons from human embryonic stem cells or from human-induced pluripotent stem cells, two cell sources referred to as human pluripotent stem cells (hPSCs). Those developments have made it possible to manufacture mDA neurons with at sufficient scale and precision to contemplate their use in cell replacement therapy for the treatment of Parkinson's disease. Our group is one of the several teams that are in the process of initiating the first human clinical trials based on the use of mDA neurons derived from hPSCs. With support from the NY state stem cell program (NYSTEM), we have implemented protocols for deriving mDA neurons under current good manufacturing practice-compliant conditions for regulatory approval of the cell-based product for human applications. We have been able to demonstrate that in vitro-derived mDA neurons can be generated under defined conditions and at large scale; that they can be cryopreserved prior to transplantation; and that the cryopreserved product is capable of reversing PD symptoms in rodent models of PD. We have further demonstrated the ability of the cells to engraft in the brain of PD monkeys and defined factors such as the shelf-life of the cells prior to and the viability of the cells after thawing and observed a lack of tumorigenic cells in the preparation. The final steps prior to initiating human trails include extensive safety studies using the fully qualified and cryopreserved mDA neuron products to get data from the exactly same batch of cells to be used for early-stage human studies. Our work sets the stage for developing an off-the-shelf cell therapy for Parkinson's disease that may develop into a valid therapeutic option for PD patients in the future.