Public Abstract:
Parkinson’s disease is a devastating disease caused by rather selective loss of brain cells that make the neurotransmitter dopamine, which controls body functions such as voluntary movement, motivation and reward, sleep, mood, attention, and learning. Parkinson’s disease is becoming more prevalent in recent years because it is an age-dependent disease and the aging population is growing in the US and world-wide. In spite of intensive research, the cause of the disease is still poorly understood and there is no effective treatment. Exciting recent developments in human stem cell biology have raised the hope for significant clinical advances in PD treatment by harnessing the power of stem cells. Pluripotent human stem cells have the potential to advance Parkinson’s disease research in two ways: 1) They could allow large-scale derivation of dopamine-producing brain cells for transplantation therapy, and 2) They could allow the establishment of relevant human brain cell-based Parkinson’s disease models amenable to disease mechanism investigation and drug screening. To achieve these vast potentials of human stem cells, we need a clear understanding of the basic molecular and cellular mechanisms directing the production of dopamine-producing brain cells from stem cells. Unfortunately, although we have some knowledge about how dopamine-producing brain cells are specified in other organisms, very little is known for their human counterparts. We propose to examine the involvement of a group of genes called familial Parkinson’s disease (FPD) genes in this process. Mutations in the FPD genes cause selective loss of dopamine-producing brain cells in Parkinson’s disease patient brain, emphasizing the importance of these genes in the development and maintenance of those disease-relevant brain cells. We recently identified a biochemical mechanism by which the FPD genes work in other organisms. We propose to test whether the same biochemical mechanism is operating in human dopamine-producing brain cells to mediate the function of the FPD genes. We will employ a combined genetic and pharmacological approach to alter this biochemical mechanism and observe its effect on the development and survival of human dopamine-producing brain cells. There are two potential outcomes of this project: 1) The development of an efficient way to promote the production of dopamine-producing brain cells from pluripotent human stem cells, and 2) the development of human dopamine-producing brain cell-based cellular models of Parkinson’s disease that recapitulates the disease process. This will help break two bottlenecks that are hampering clinical advances in Parkinson’s disease therapy and fulfill the mission of the Basic Biology Initiatives, which is to facilitate the realization of the vast potential of human stem cells as tools for biochemical innovation and disease treatment through basic research.
Statement of Benefit to California:
Parkinson’s disease is a crippling brain disorder that robs patients of their control of voluntary body movement, among other qualities of life. It is estimated that between 1 million and 1.5 million people are living with Parkinson’s disease in the US, with approximately 50,000 living in California. With the number of baby boomers reaching retirement age rapidly increasing, cases of this age-related disease is going to escalate in the coming years. Currently there is no cure for this disease. Although a number of pharmacological and surgical treatments are available to patients, they all have serious side effects. Effective treatment of Parkinson’s disease requires targeting of the root cause of the disease: the relentless loss of dopamine-producing brain cells. The goal of this research proposal is to understand the basic biology underlying the production and maintenance of human dopamine-producing brain cells from stem cells. Possible outcomes from this research project, including the development of an efficient strategy to enhance the production of dopamine-producing brain cells and the establishment of human brain cell-based cellular models of Parkinson’s disease, will help realize the great potential of pluripotent human stem cells in regenerative medicine. This research project could benefit California in several ways: 1) it has the potential to provide a novel treatment for Parkinson’s disease by targeting the underlying cause of disease, offering a potential cure. This could result in saving of tremendous amount of health care costs provided to Parkinson’s disease patients and their caretakers; 2) if the candidate compounds we are testing show clinical benefits for Parkinson’s disease, they will be eventually commercialized in California. This will benefit the state financially, create jobs for local economy, and improve the quality of lives of its citizens; 3) whenever possible, we will purchase California-made equipment, supplies, and reagents for this research; 4) this research involves collaboration with some of the pioneers in stem cell biology and Parkinson’s disease research in California. It has a high probability of success and will help maintain California’s status as the national and world leader in stem cell research.
Review Summary:
EXECUTIVE SUMMARY
This proposal is focused on the important clinical problem of Parkinson’s Disease (PD) and the therapeutic potential envisioned by the transplantation of dopaminergic (DA) neurons derived from human pluripotent stem cells (hPSC). The applicant suggests that a bottleneck to successful treatment of PD lies in the production and long-term survival of differentiated DA neurons for transplantation. The applicant proposes to leverage the finding that a group of familial Parkinson's Disease (FPD) genes function in translational control, and hypothesizes that loss of normal translational control affects differentiation and survival of DA neurons. The proposal has three specific aims: In Aim 1, the applicant will use hPSCs to test the hypothesis that loss of function and/or gain of function of certain FPD genes plays an important role in human DA neuron differentiation and/or survival. In Aim 2, the roles of translational control pathways in mediating the effects of these specific FPD genes will be tested. Finally, in Aim 3, the applicant plans to assess the effects of clinically tested translational inhibitors in promoting DA neuron differentiation and survival.
Reviewers commented that PD is a devastating disease caused by selective loss of DA neurons and that our present understanding of the basic biological mechanisms underlying human DA neuron differentiation and survival is limited. Reviewers were in agreement that the hypothesized role of FPD genes in translational control of DA neuron biology is an innovative hypothesis. However, reviewers commented that the idea of focusing on DA neuron differentiation in the study of PD as presented by the applicant is not scientifically sound, since the loss of DA neurons in adult brains does not per se argue for a differentiation defect. Reviewers did find the question how FPD genes function in DA neuron survival to be relevant to understanding PD, but not to be a focus of this RFA.
In terms of feasibility, reviewers found multiple deficiencies in both the preliminary data and the experimental design that limited the potential for the proposed studies to produce interpretable results. For instance, one reviewer pointed out that one of the aspects critical to this research proposal, is the effect of genetic manipulations on the numbers of DA neurons. However, the preliminary data often lack a description of which neurons are being analyzed or how they are being recognized. Moreover the sample size is not identified, and statistical tests used to arrive at significance are not specified. In addition, tyrosine hydroxylase, which is repeatedly used as the only marker of DA neurons, is not specific enough as this enzyme is expressed in all catecholamine-producing cells. With regard to experimental design, reviewers had concerns about the lack of specificity of the manipulations proposed to test the role of translational control pathways in mediating the effects of the FPD genes. They pointed out that the proposed manipulations will affect a number of signaling pathways and that adequate controls to discriminate between specific effects on DA neuron differentiation versus non-specific global effects on differentiation and survival are lacking. A further weakness is the plan to manipulate translational control pathways in PD-specific induced pluripotent stem cells, which may not be informative if these cells do not develop a disease phenotype in culture.
Reviewers praised the principal investigator’s (PI) strong track record in neural degeneration and especially PD research. The PI has an extensive publication record and his/her research is supported by numerous grants. Moreover, the PI has chosen three excellent co-investigators/collaborators who are experts in three of the relevant fields necessary to accomplish the goals in this application. The main concern related to the high level of commitment of the PI to the already funded projects.
Overall, reviewers found this application to be based on an interesting hypothesis about DA biology. However, there were many weaknesses in the rationale, preliminary data and experimental design that raised concerns about the project’s feasibility and diminished the quality of the application.
