New Faculty II
$1 830 391
The goals of this study are to develop patient-specific cell lines from patients with Parkinson’s disease (PD) with defined mutations and sporadic forms of the disease. These lines will be used as an experimental pre-clinical model to study cellular phenotypes and disease mechanisms unique to PD. The specific objectives of these studies are to (1) demonstrate the feasibility to generate patient-specific cell lines from skin cells of patients, (2) show that these cells have the ability to differentiate into specific brain cells relevant for PD, (3) demonstrate intrinsic differences and biological processes of these cells compared to controls, and (4) show that these cells are capable to improve symptoms of PD in pre-clinical models. Reprogramming of adult skin cells to a pluripotent state is the technique we are using in this proposal. Derivation of patient-specific pluripotent cell lines eliminates many challenges (e.g. source of tissue and cells, immune reaction and ethical considerations) and becomes an attractive avenue of research. We have no cure for PD, or good long-term therapeutics without deleterious side-effects. Therefore, there is a great need for novel therapies to halt or reverse the disease, which could be cell replacement therapy.
Statement of Benefit to California:
This proposal provides real benefits and value to the state of California and its citizens in providing new approaches for stem cell therapy in Parkinson’s disease (PD). Reprogramming of adult skin cells to a pluripotent state is the underlying mechanism where this application is build on. Derivation of patient-specific pluripotent cell lines eliminates many challenges (e.g. source of tissue and cells, immune reaction and ethical considerations) and becomes an attractive avenue of research. Approx. 36,000-60,000 people in the State of California are affected with this neurodegenerative disease that causes a high degree of disability and financial burden for our health care system. It is estimated that the number of PD cases will double by the year 2030. With this research project, we will evaluate patient-specific pluripotent cell lines in various pre-clinical conditions to get closer to therapeutic applications for PD, for which we have no cure for or adequate long-term therapies to date.
The goal of this application is to investigate the derivation of induced pluripotent stem (iPS) cell lines from patients with sporadic forms of Parkinson’s disease (PD) and from patients with defined mutations in the most relevant PD-causing gene. In the three initial aims of the proposal, these lines will be used as an experimental pre-clinical model to study cellular phenotypes and disease mechanisms unique to PD. Aim 1 in this application will be to demonstrate the feasibility of generating patient-specific cell lines from skin cells of patients. Aim 2 is to derive the iPS cells into specific dopaminergic neurons in order to (Aim 3) assess for differences in biological processes of these cells compared to controls. Last aim proposed will be to transplant the neurons derived from PD patients or normal backgrounds in a standard animal pharmacologic model of PD (6-OHDA injection) in order to demonstrate that these cells are capable of improving symptoms of PD in such models. In terms of the research plan, reviewers agreed that the proposal is interesting and takes good advantage of recent findings and local resources. However, despite being well structured, the research plan was felt to lack depth and presents a number of inherent problems, mostly resulting from a lack of detail in the experimental design. One of the main weaknesses of this application lies in the design of the last aim. It is not clear that grafting in a chemical PD environment (6-OHDA) for 3 months will be sufficient to inform any differences among the idiopathic and the mutant forms of the disease. Moreover, the applicant does not acknowledge the difficulties reported in the field for obtaining adequate survival of human embryonic stem cell (hESC)-derived DA neurons in 6-OHDA-lesioned animals, and thus does not offer alternatives should the cells not survive. In addition the 6-OHDA model probably lacks the sensitivity required in order to highlight the probable subtle differences in survival and function of grafted cells. More importantly, the time frame planned for in vivo observation of the iPS derived DA neurons is inadequate (3 months), especially when the cells of origin (iPS) derive from an adult onset disease. Reviewers also felt that the post-implantation assessment of the cells as outlined in the proposal is extremely poor and completely lacking in experimental detail. An additional concern is the lack of transplant expertise in the applicant’s lab. For example there is no presentation concerning the rationale for the number of cells to be transplanted, or the potential influence of immune suppression on graft survival and/or functional outcomes. Also there is no consideration of exactly what state of differentiation the cells will be in when transplanted and it appears from the application that the cells may be fully differentiated neurons, which generally do not survive transplantation. In terms of qualifications, the principal investigator (PI) has good training in human genetics and reviewers found the publication record of the applicant appropriate for the stage of career. A mentoring plan is in place and the roles of the mentors are well defined. However, reviewers expressed concern at the lack of significant background in neurosciences, neurodegenerative disease, or stem cell biology, and the fact that the applicant will rely extensively on other researchers for this expertise. The institution has provided the applicant with appropriate research space and tissue culture facilities. However, reviewers had some concern in terms of the institutional track record and future plans. The applicant’s institution claims to be a world recognized institution for bench to bedside research on Parkinson’s disease. It is part of a CIRM-sponsored Center, but the application lacked information about the extent to which the institute plays a substantial role in this center, and the extent to which the applicant will have access to the center’s shared facilities.