Year 2

Parkinson’s disease (PD) is a devastating movement disorder caused by the death of dopaminergic neurons (a type of nerve cells in the central nervous system) present in the midbrain. These neurons secrete dopamine (a signaling molecule) and are a critical component of the motor circuit that ensures movements are smooth and coordinated.

All current treatments attempt to overcome the loss of these neurons by either replacing the lost dopamine, or modulating other parts of the circuit to balance this loss or attempting to halt or delay the loss of dopaminergic neurons. Cell replacement therapy (that is, transplantation of dopaminergic neurons into the brain to replace lost cells and restore function) as proposed in this application attempts to use cells as small pumps of dopamine that will be secreted locally and in a regulated way, and will therefore avoid the complications of other modes of treatment. Indeed, cell therapy using fetal tissue-derived cells have been shown to be successful in multiple transplant studies. Work in the field has been limited however, partially due to the limited availability of cells for transplantation (e.g., 6-10 fetuses of 6-10 weeks post-conception are required for a single patient).

We believe that human pluripotent stem cells (PSC) may offer a potentially unlimited source of the right kind of cell required for cell replacement therapy. Work in our laboratories and in others has allowed us to develop a process of directing PSC differentiation into dopaminergic neurons. To move forward stem cell-based therapy development it is important to develop scale-up GMP-compatible process of generating therapeutically relevant cells (dopaminergic neurons in this case).

During this grant, we have optimized a step-wise scalable process for generating authentic dopaminergic neurons in defined media from human PSC, and have determined the time point at which dopaminergic neurons can be frozen, shipped, thawed and transplanted without compromising their ability to mature and provide therapeutic benefit in animal models. Our process has been successfully transferred to a GMP facility and we have manufactured multiple lots of GMP-equivalent cells using this process. Importantly, we have shown functional equivalency of the manufactured cells in appropriate models. The tools, reagents and processes we have developed in this project allow us to move towards translational therapy and establish processes that could be applied to future IND-enabling projects. In addition, the processes we have developed would be of benefit to the CIRM community.