Disease Team Research I
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 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. 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. Parallel efforts by clinicians have identified processes to implant the cells safely and to follow their behavior in humans in a safe non-invasive fashion. Equally important, useful animal models for testing cell therapy have been developed. We therefore believe that the time is right to mount a coordinated team effort such as the one we have proposed to approval from the FDA to treat PD using dopaminergic neurons obtained from hESCs. For this proposal we have built a California team with both scientists and clinicians that have the potential to translate a promising idea (a cell therapy for PD) to an IND submission. Our goals include: 1) Identifying a clinically compliant hESC line capable of differentiating into midbrain dopaminergic neurons; 2) Developing protocols for generating and purifying dopaminergic neurons on a large scale; 3) Transferring the protocols to a Good Manufacture Practice (GMP) facility and making clinical grade lots; 4) Testing the quality of the cells in suitable PD animal models (rodents and large animal models); 5) Collecting the data to submit to the FDA for permission to conduct a clinical trial. This application to treat a currently non-curable disease (PD) meets CIRM's primary goal for Disease Team Research Awards and we believe our efforts will help take cell-based therapy for PD to the clinic.
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. We have assembled a California based team of scientists and clinicians that aim to develop a cell replacement therapy for this currently non-curable disorder. We believe that this proposal which will hire more than thirty employees in California 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 and we will select California-based companies for commercialization of such therapies. 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.
The goal of this proposal is to develop clinical grade dopaminergic neurons from human embryonic stem cells (hESCs) for the treatment of patients with Parkinson’s disease (PD). PD is a neurodegenerative disorder caused by the loss of midbrain dopaminergic neurons. Currently, there are no cures for PD although several symptomatic treatments are available. Since the early 1980’s, transplantation of dopaminergic neurons into the brain to replace lost cells and restore function has been evaluated as a promising therapy for PD. Efforts with cell transplantation have stalled primarily because of three major challenges: variable efficacy, undesirable side effects, and a lack of a reliable source of human cells. hESCs, which can proliferate indefinitely in culture and differentiate into any somatic cell type, offer a promising potential cell source for transplantation. To achieve the goal of this proposal, the applicant plans to identify a clinically compliant hESC line capable of differentiating into midbrain dopaminergic neurons and to optimize scalable protocols for the generation and purification of Good Manufacturing Practice (GMP)-compliant dopaminergic neurons from these cells. The applicant will then evaluate these neurons for efficacy and safety in small and large animal models of PD, and will determine the requirement for immune suppression. Based on these studies, the applicant will then develop an Investigational New Drug (IND) application for submission to the Food and Drug Administration (FDA). Overall, reviewers agreed that this proposal has a sound scientific rationale based on decades of tissue and cell transplantation work in this field. However, important gaps in the preliminary efficacy data and the research plan lowered the panel’s expectation of an IND filing within the four-year timeframe. The application was not recommended for funding. Reviewers agreed that a significant body of research and clinical data supports the applicant’s rationale to replace the loss of midbrain dopaminergic neurons in PD. They commented that the application builds on several decades of transplantation work in both preclinical models and human subjects. While human trials have demonstrated proof of concept, they have highlighted two issues. First, that efficacy is variable among patients, and that side effects have emerged, notably dyskinesias. Because hESC-derived dopaminergic neurons may circumvent the side effects observed in the initial trials of cell replacement approaches, reviewers felt the use of hESCs was justified. The significance of the proposal was noted by reviewers, as the proposed therapeutic addresses an unmet medical need and has potential for great impact. PD is a common disease with no available disease modifying medical or surgical therapies. Current medical and surgical therapies are effective in the control of PD symptoms at least in the first few years after onset. However, their long-term efficacy diminishes as degeneration of dopaminergic cells progresses. Reviewers evaluated two key aspects of the preliminary data, 1) the production of a more pure and expandable source of dopaminergic cells than has been used previously, and 2) the preliminary efficacy data, both of which address key bottlenecks in advancing a successful therapy. First, reviewers noted the applicants’ solid demonstration of the ability to generate dopaminergic neurons by a four-step process using xenogeneic-free reagents. The process was described as scalable by the applicant, but insufficient details were presented in the application regarding how scalability would be achieved. The purity of hESC-derived dopaminergic neurons achieved after sorting was approximately 80% by TH immunohistochemistry. However, no evidence was presented about the rate of production of dopaminergic neurons of the A9 phenotype, which has been shown in the literature to be the appropriate dopaminergic cell for transplantation in PD. Reviewers also raised concerns about the preliminary efficacy data. Although the applicant demonstrates improvement in rotational behavior at 12 and 16 weeks post transplantation, a substantially later time point than with conventional tissue sources, reviewers noted the critical lack of sensorimotor testing for functional efficacy. This was judged to be an important omission in the plan, since there is a well-established battery of sensorimotor tests that better reflect the human condition than rotational behavior in the rodent model of PD. Finally, reviewers commented that the plan should include an assessment of efficacy in the dyskinesia rodent model in addition to the standard 6-hydroxydopamine (6-OHDA) model of PD. This must be included to assess the development of severe dyskinesias, one of the most serious side effects of early neural tissue transplantation in humans. The research and development plan was well explained, and outlined graphically in the application. Reviewers praised the inclusion of preclinical studies in a large animal model, which will be crucial before embarking on a clinical trial in PD patients. However, reviewers mentioned that the time allotted for large animal experiments may not be sufficient, as testing for efficacy and the development of side effects, such as onset of dyskinesias, will very likely take longer than planned. Reviewers commented that long-term follow-up in both the rodent and the large animal models is necessary to test for the long-term stability of the hESC-derived dopaminergic neurons, tumor formation and migration. They also felt that these large animal studies should occur earlier in the timeline and result in a go/no go decision point. The panel was concerned that immunosuppression was insufficiently addressed in the application. Finally, necessary improvements to the plan include those discussed in the preceding paragraph: optimization of differentiation protocols to produce A9 dopaminergic neurons, inclusion of sensorimotor testing, and the addition of studies in the dyskinesia rodent model. From a regulatory perspective, reviewers judged the project plan to be practical, targeting key obstacles in a logical order. Manufacturing methods appeared sufficiently well established to enable GMP production. Cell selection methods in development are currently used in clinical-scale manufacturing of cell therapy products, and reagent issues have been or are being addressed. Proposed milestones and a timeline were clearly stated. For the most part timelines seemed realistic, with the notable exceptions of the large animal studies and the time available for development of the GMP/clinical manufacturing methods. Clear go/no-go decision criteria at milestones were lacking. Reviewers found that the principle investigator (PI) and the two Co-PIs have the necessary expertise and track record to provide leadership for this project. One reviewer, however, was concerned about the PI’s lack of expertise in directing a clinically oriented project such as this one. On the other hand, another reviewer praised the PI’s 45% time commitment to the project. The significant regulatory expertise present in the team members was viewed as a strength, as were the clear governance structure and the enlistment of an experienced project manager to coordinate the activities of the different researchers and institutions. This is a multidisciplinary collaborative project from several industry and academic institutions. Reviewers agreed that each institution has the necessary infrastructure and facilities to support their assigned projects. The resources and budget were found to be adequate to complete the proposed project. Overall, reviewers agreed that this proposal addresses an important unmet medical need and could potentially have a significant impact. However, they were not convinced that sufficient convincing preliminary data was presented in the application to justify moving forward with this award. As a result, the panel did not believe the proposal would result in an IND filing within the four-year timeframe.