Parkinson’s disease is a devastating neurodegenerative disorder for which there is no cure. Several foundations including the Michael J. Fox Foundation have identified cell therapy as one possible avenue for research as cell therapy using fetal tissue-derived cells has been shown to be successful in multiple transplant studies. Work in the field had been limited however, due to the limited availability of cells for transplantation as cells from 6-10 human fetuses of 6-10 weeks post-conception is required for a single patient.
Human embryonic stem cells offer a potentially unlimited source of the right kind of cell required for cell replacement therapy due to their remarkable ability to self-renew (they can divide indefinitely in culture) and to be trained to become any cell type of the body. In this proposal we seek to understand how human embryonic stem cells differentiate into authentic dopaminergic neurons using a culture method that we have tested. We believe that this differentiation can be broken into several stages each of which is regulated by growth factors and other molecules. We also believe that these stages can be understood by selecting cells at each stage and comparing their properties using molecular tools and by examining their behavior after transplanting the cells into a mouse disease model. In addition, we will need to develop a noninvasive method of following cells after transplantation and we propose to develop a TH-ferritin (that can be detected by magnetic resonance imaging, MRI) reporter line based on previous successful work in mice to monitor dopaminergic neurons in animal models and possibly in future clinical trials. We believe that these experiments are critical to enhancing our understanding of the disease and providing the tools that will be necessary to move cell therapy to the clinic.
Statement of Benefit to California:
We have proposed three aims in this proposal to develop markers that can distinguish stages in the process of development, to develop reporter lines that allow us to isolates cells at each specific stage of differentiation, and to identify the optimal cells for therapy using animal models that mimic the human disease. We have also proposed to assess the long-term integration and differentiation of transplanted cells using a magnetic resonance imaging (MRI)-based labeling system.
We believe these experiments not only provide a blueprint for moving towards the clinic for Parkinson’s disease sufferers but also a generalized plan for how cell therapy will need to be developed for treatment of multiple disorders including motor neuron diseases and spinal cord injury. The tools and reagents that we develop will be made widely available to Californian researchers and we will select California-based companies for commercialization of such therapies. We will hope that it is California-based physicians who will be at the forefront of developing this promising avenue of research. We expect that the money expended on this research will benefit the Californian research community, and the tools and reagents we develop will help accelerate the research of our colleagues in both California and worldwide.