Early Translational II
Parkinson's disease (PD) is a devastating movement disorder caused by the death of dopaminergic neurons (a type of nerve cells in the central nervous system) present in the midbrain. These neurons secrete dopamine (a signaling molecule) and 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 (that is, transplantation of dopaminergic neurons into the brain to replace lost cells and restore function) as proposed in this application attempts to use cells as small pumps of dopamine that will be secreted locally and in a regulated way, and will therefore avoid the complications of other modes of treatment. Indeed, cell therapy using fetal tissue-derived cells have been shown to be successful in multiple transplant studies. Work in the field has been limited however, partially due to the limited availability of cells for transplantation (e.g., 6-10 fetuses of 6-10 weeks post-conception are required for a single patient). We believe that human embryonic stem cells (hESCs) may offer a potentially unlimited source of the right kind of cell required for cell replacement therapy. Work in our laboratories and in others has allowed us to develop a process of directing hESC differentiation into dopaminergic neurons. To move forward stem cell-based therapy development it is important to develop scale-up GMP-compatible process of generating therapeutically relevant cells (dopaminergic neurons in this case). The overall goal of this proposal is to develop a hESC-based therapeutic candidate (dopaminergic neurons) by developing enabling reagents/tools/processes that will allow us to translate our efforts into clinical use. We have used PD as a model but throughout the application have focused on generalized enabling tools. The tools, reagents and processes we will develop in this project will allow us to move towards translational therapy and establish processes that could be applied to future IND-enabling projects. In addition, the processes we will develop would be of benefit to the CIRM community.
Statement of Benefit to California:
Parkinson’s disease affects more than a million patients United States with a large fraction being present in California. California, which is the home of the Parkinson’s Institute and several Parkinson’s related foundations and patient advocacy groups, has been at the forefront of this research and a large number of California based scientists supported by these foundations and CIRM have contributed to significant breakthroughs in this field. In this application we and our collaborators in California aim propose to develop a hESC-based therapeutic candidate (dopaminergic neurons) that will allow us to move towards translational therapy and establish processes that could be applied to future IND-enabling projects for this currently non-curable disorder. We believe that this proposal includes the basic elements that are required for the translation of basic research to clinical research. We believe these experiments not only provide a blueprint for moving Parkinson’s disease towards the clinic for people suffering with the disorder but also a generalized blueprint for the development of stem cell therapy for multiple neurological disorders including motor neuron diseases and spinal cord injury. The tools and reagents that we develop will be made widely available to Californian researchers. 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.
This is a Development Candidate application focused on the development of a scalable process for the production of dopaminergic (DA) neurons from human embryonic stem cells (hESCs) for the treatment of Parkinson’s disease (PD). The applicants propose four specific aims. In Aim 1, they will select a clinically compliant hESC line capable of differentiating into DA neurons. During Aim 2, they plan to optimize scalable protocols for the generation and purification of authentic A9 DA neurons from hESCs. In Aim 3, they will develop a scalable process under good manufacturing practices (GMP)-compatible conditions for the production of DA neurons. Finally, in Aim 4, the applicants plan to assess the equivalency of cells manufactured under the cGMP-compatible processes with cells generated at laboratory scale. Reviewers agreed that this proposal addresses a significant, unmet medical need and, if successful, could have a profound impact. PD is a devastating disease for which no disease modifying therapies exist and only symptomatic treatments (that worsen with disease progression) are available. Reviewers found the scientific rationale for the proposal to be clear and reasonable. On the other hand, there was some concern that significant questions remain about the appropriate cell type and the purity and safety of a cell therapy product, which could be generated from hESCs. However, in line with the priorities of the RFA, most reviewers found this to be a high impact project with a clearly defined development candidate, and highest human stem cell relevance. In general, reviewers agreed that the proposed research is feasible and praised the team for the plan and the very clearly outlined milestones. Reviewer confidence in the ability of these investigators to carry out the proposed research was further enhanced by the content and quality of the preliminary data. Moreover, most reviewers agreed that despite the plan’s ambitiousness, it is well focused, achievable within the 3-year period and will likely lead to a development candidate to take forward into IND-enabling preclinical development. Concerns were expressed about the feasibility of generating “authentic” A9 DA neurons and of completely eliminating undifferentiated cells with potential to form teratomas. Additionally, concerns were raised about the adequacy of proposed preclinical in vivo models, which were limited to rodent models, and about the lack of adequate discussion of potential pitfalls and alternative plans. Reviewers found the PI’s expertise and publication record to be appropriate for the proposed work. Notably, the PI has recently produced several publications that form the basis for this proposal. The Co-PI was also found to be appropriate for the work proposed, and some reviewers considered that s/he will lend important expertise in the development and production of the desired DA cell line. In terms of the team and collaborations, reviewers found them all to be appropriate, well defined and essential to the proposed work. Institutional support was considered excellent as well. Overall reviewers found this proposal feasible, with strong preliminary data and straightforward research plan. Reviewers expressed some concerns about the ability to obtain fully functional GMP-compatible “authentic” A9 DA neurons in the time allotted. Nevertheless, reviewer confidence in the strong research team and the project’s high potential impact provided a compelling basis for the support of this project.