CIRCUITRY REPAIR IN PARKINSON’S DISEASE: FROM STEM CELL REPLACEMENT TO AXONAL TARGETING USING STEM CELL MODELS

Neurodegenerative diseases are debilitating conditions that result in dysfunction and loss of nerve cells.

The brain has a very limited capacity for self-repair, and there is an unmet need for finding new therapeutic strategies.

My team has been successful in generating dopamine (DA) neurons from pluripotent stem cells, and our work have been a main driving force for first-in-human clinical trials in Parkinson’s Disease (PD).This projects in this proposal are designed to capture the momentum in the field and work towards developing more refined stem cell differentiation protocols and better translational strategies with the final aim to achieve more complete circuitry reconstruction and repair.

As we are embarking on these new projects, we would like to explore the possibility to conduct the majority of the studies in vitro, rather than in long-term xenograft models.To achieve this, we will make a targeted effort to molecularly and functionally define DA subtype identity, which will enable us to perform unbiased screens in organoid models, as well as to explore advanced cell culture methods and microfluidic based approaches to mimic DA circuitry in 2D and 3D cell models.

Combined, this will provide an alternative method to in vivo xenograft models to validate stem cell differentiation and study circuitry repair in vitro. The results will be used to devise a translational approach for homotopic grafting aimed at circuitry repair in PD