Disease Team Therapy Development - Research
We proposes to use human embryonic stem cells (hESCs) differentiated into neural progenitor/stem cells (NPCs), but modified by stably programming the cells with the transcription factor MEF2C to drive them more specifically towards dopaminergic (DA) neurons, those lost in Parkinson’s disease. We will select Parkinson’s patients that no longer respond to L-DOPA and related therapy for our study, because no alternative treatment is currently available. The transplantation of cells that become DA neurons in the brain will create a population of cells that secrete dopamine, which may stop or slow the progression of the disease. In this way, moderate-to-severely affected Parkinson’s patients will benefit. The impact of development of a successful cell-based therapy for late-stage Parkinson’s patients would be very significant. There are approximately one million people in the United States with Parkinson’s disease (PD) and about ten million worldwide. Though L-DOPA therapy controls symptoms in many patients for a period of time, most reach a point where they fail to respond to this treatment. This is a very devastating time for sufferers and their families as the symptoms then become much worse. A cell-based therapy that restores production of dopamine and/or the ability to effectively use L-DOPA would greatly improve the lives of these patients. Because of our extensive preclinical experience and the clinical acumen of our Disease Team, we will be able to quickly adapt our procedures to human patients and be able to seek FDA approval within four years.
Statement of Benefit to California:
It is estimated that the cost per year for a Parkinson’s patient averages over $10,000 in direct costs and over $21,000 in total cost to society (in 2007 dollars). With nearly 40 million people in California and with one in 500 estimated to have Parkinson’s (1.5-2% of the population over 60 years of age), there are approximately 80,000 people in California with Parkinson’s disease. Thus, Parkinson’s disease is a significant burden to California, not to mention the devastating effect on those who have the disease and their families. A therapy that could halt the progression or reverse Parkinson’s disease would be of great benefit to the state and its residents. It would be particularly advantageous if the disease could be halted or reversed to an early stage, since the most severe symptoms and highest costs of care are associated with the late stages of the disease. Cell-based therapies offer the hope of achieving this goal.
The objective of this project is to complete preclinical studies and file an Investigational New Drug (IND) application for a cell therapy treatment for Parkinson’s Disease (PD) in patients who no longer respond to dopamine replacement therapy. Currently, medications, surgery, and multidisciplinary management can relieve symptoms in PD. Cell transplantation has been explored in PD clinical trials with mixed results. The proposed approach uses human embryonic stem cells (hESCs) that have been genetically modified to express an active form of the transcription factor Myocyte Enhancer Factor 2C (MEF2C) and subsequently differentiated into neural progenitor cells (NPCs) for transplantation. The applicant asserts that MEF2C-overexpression will drive differentiation of neural stem cells more specifically towards dopaminergic neurons, which are the population that is lost in PD. Proposed project milestones include completing the manufacturing, preclinical, and regulatory activities required to file an IND with the Food and Drug Administration (FDA) within four years. Significance and Impact - The proposed therapeutic addresses a highly unmet medical need, especially considering that the approach is intended for patients who have become unresponsive to dopamine replacement therapy. - Some reviewers saw this approach as not significantly novel and therefore of limited potential impact over other therapeutic approaches under development. - The potential impact of this approach is unclear, as reviewers were not able to discern whether the proposed therapy would avoid the adverse side effects that have been observed in other cell transplantation studies for PD. - Important details regarding the implementation and duration of the immune suppression strategy are not elaborated in the Target Product Profile. Rationale - The rationale for cell therapy to provide dopamine is clear and well established; however, no convincing data are provided to demonstrate why MEF2C expression is a better approach than the best available method for deriving dopamine-producing cells. - The preliminary data provided for efficacy were not convincing. Data were shown for only one of the two behavioral study models. Only modest improvements were seen in vivo which barely reached a statistically significant difference from the control. - A reviewer noted that the preclinical behavioral experimental data provided were difficult to interpret, as it was unclear whether the described improvements were due to the effects of transplanted cells or from sprouting of residual fibers that may not have been completely lesioned. -Reviewers noted that data from several recent publications raise the possibility that serotonin modulation could be contributing to some of the observed effects, which was not discussed by the applicant. Therapeutic Development Readiness -The applicant has not shown definitive proof of concept linking dopamine production by transplanted cells with an improved outcome in vivo. - Reviewers were concerned about the purity of the proposed development candidate and the poor characterization of other cell types in the population. The application lacked detailed cell characterization. - Reviewers felt the project is at an early stage of therapeutic development readiness. - Research scale feasibility data is shown but the master cell bank has not yet been developed which must then be qualified and tested. - One lot of cells appears to be sufficient to treat only a single patient. Production methods may be adequate to get to an IND filing and conduct safety studies but the ability to scale up to conduct later phase clinical trials is unclear. - Reviewers felt it was premature to conduct studies using a clinically relevant animal model. Furthermore, the panel disagreed with the applicant statement that two preclinical models would necessarily be required by the FDA. Feasibility of the Project Plan -Feasibility of the project plan was questioned in light of the limited characterization of the product. There was no discussion of product heterogeneity, transgene copy number, and other important aspects of the cell population. -The application lacked data demonstrating duration of MEF2C transgene expression in vivo. Furthermore, the proposal did not address the possibility of gene silencing in vivo and resulting loss of efficacy. - One reviewer disagreed with the method proposed to determine the dose for the clinically relevant animal model. It was suggested to perform the lesion and then dose to see an effect rather than extrapolating the dose from other preclinical models. -If the transplanted cells exert their effect through a neurotrophic mechanism, then it would be important to consider this in the clinical trial design. Principal Investigator (PI) and Development Team - Reviewers agreed that the PI is an established and qualified researcher in neurodegenerative disease; however some reviewers were concerned about the PI’s lack of experience in developing a cell therapy product for clinical transplantation. - Although reviewers were impressed by the quality of consultants engaged, it was unclear what role some of those identified would play in the project. Collaborations, Resources and Environment - The designated Good Manufacturing Practices (GMP) production facility was viewed favorably for being a highly qualified and capable contractor. - The intellectual property status and whether the applicant would have freedom to operate with the proposed cell line and/or the viral vector used was not fully addressed. Although this was not judged to be a barrier to the ability to conduct the proposed studies, this would need to be clarified for further product development. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. ) - Reviewers felt the budget for the proposed Good Laboratory Practice (GLP) rodent studies and for the clinically relevant studies was excessive. Conditions Applied by the Planning Award Grants Working Group - The Planning Award GWG set a condition that “to be eligible for the Disease Team Therapy Development Research Award competition, the applicant must provide at the time of Full Application convincing preclinical evidence for the identity and survival of hESC-derived A9 dopaminergic neurons in the striatum, with histological data showing robust neurite outgrowth (3-5 mm from graft, volumetric evaluation) and synaptic connections with the host brain”. - Reviewers did not find the histological data provided in response to the conditions of the Planning Award to be convincing. However, the GWG felt that condition had been addressed sufficiently to permit eligibility and scoring of the application.
- A motion was made to move the proposal to Tier 1 (recommended for funding). Reviewers reiterated the concerns with the proposal, including the low percentage of therapeutic candidate cell, poorly characterized cell population, and unconvincing preliminary data. It was pointed out that many medical innovations have been made without having understood mechanism of action and whether expectations should be set differently for a patient population in greater need. One reviewer noted that the scores across the reviewers were fairly consistent and in a range that is typically not considered fundable. It was pointed out that there are currently three other projects in CIRM’s translational portfolio related to PD. In light of increasing and evolving research activity in PD and this being viewed as premature for a translational award, this proposal was not viewed as worthy of such a large investment.
- The motion failed.
- Russell Lonser
- David Pepperl
- Darin Weber