Early Translational I
ICOC Funds Committed:
Parkinson’s disease (PD) is a devastating movement disorder caused by the death of dopaminergic neurons, a specific subtype of neurons in the brain. These neurons secrete dopamine (a signaling molecule) and among higher brain functions 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 (e. g. transplantation of dopaminergic neurons into the brain to replace lost cells and restore function) as proposed in this application attempts to use cells to release small amounts of dopamine to a specific brain area to provide appropriate activation of the affected motor circuitry. It is firmly established from experimental evidence in animal studies and human trials that dopaminergic cell replacement is a realistic strategy. However, some clinical studies have reported only variable success. Most transplantation studies into Parkinson patients have used cells from tissue chunks of human fetal brains pooled from multiple aborted fetuses. We therefore conclude from these results that a therapeutic dopaminergic cell type is present in these grafts but their precise identity is not known (perhaps pliable dopamine progenitor cells engraft better than mature neurons). Likely, these studies grafted variable proportions of dopamine neurons without control over the presence of other, potentially counteracting, neuronal subtypes. To date there are no ways to purify and specifically test dopamine neurons or their precursor cells. This is the key stumble block that hinders the development of an investigational new drug (IND) for cell replacement in PD. We will therefore first develop methods to isolate and functionally test dopamine neurons and their progenitors and thereby identify and refine the development candidate for successful cell therapy. The isolation of a drug from aborted human embryos is complicated by enormous logistic and technical complications, ethical considerations, and potential immunerejection of the graft. We will use induced pluripotent stem (iPS) cells derived from the patients’ own skin to derive defined and genetically-matched dopamine neuronal populations in a scalable manner. In addition, from the same iPS cells we will generate transplantable neural cells to serve as small, regulated pumps of growth factors that have been shown to inhibit dopamine neurons from degenerating but lack of efficient delivery has hindered clinical application. In this proposal, we have assembled a strong California team of stem cell biologists, developmental neurobiologists, clinicians, and a for-profit company whose combined efforts are realistic to develop novel, preclinical candidates of individualized cell-based therapies for PD.
Statement of Benefit to California:
We have assembled a team of scientists and clinicians that aim to develop a cell transplantation therapy for a currently non-curable disease, Parkinson’s disease, using patients’ skin-derived pluripotent stem cells. We believe that this proposal includes the basic elements that are required for the translation of basic research to clinical research. We have proposed to obtain pluripotent stem cells from skin in a safe manner which is prerequisite of Food and Drug Administration (FDA)-approval for clinical use of this important stem cell type. This will provide California’s academic and commercial community with the potential to generate these pluripotent stem cells from patients suffering from a variety of different diseases in a way that is compatible for clinical use to treat a number of diseases including Diabetes, spinal chord injury, and genetic skin and muscle diseases. Further, we plan to develop two therapeutic cell populations which will be tested in preclinical studies for efficacy and safety and refined to become candidate drugs to be tested in further clinical settings. Although transplantation will not cure many of the more general symptoms associated with Parkinson’s disease, specific features of the movement disorder will be responsive to the treatment. As currently 1-2% of the population older than 65 years is diagnosed with this devastating neurodegenerative disease, any progress towards relieving the major motor symptoms of Parkinson patients will be of immense benefit to the State of California and its citizens. In addition, all the tools and reagents that we develop will be made widely available to Californian researchers and we have selected a California-based company for potential commercialization. We hope that California-based physicians 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.