We proposes to use human embryonic stem cells (hESCs) differentiated into neural progenitor/stem cells (NPCs), but modified by transiently programming the cells with the transcription factor MEF2C to drive them more specifically towards dopaminergic (DA) neurons, representing the cells 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 an IND from the FDA within four years.
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 goal of this project is to complete ongoing preclinical research and development activities and to file an IND for a therapeutic candidate for treatment of Parkinson’s Disease (PD) in patients that no longer respond to dopamine replacement therapy. The proposed development candidate consists of human embryonic stem cells (hESC) that have been differentiated into neural stem/progenitors (NPC), which are subsequently programmed by transient exposure to Myocyte Enhancer Factor 2C (MEF2C) to drive them more specifically towards the A9 dopaminergic (DA) neuron phenotype. The planning phase includes meetings between team members, consultants and regulatory advisors to prepare a detailed preclinical development plan and timeline.
Significance and Impact
- The creation of a stable, safe cell line with an A9 dopaminergic phenotype represents a major goal in the field of cell transplantation for PD. The proposed strategy is reasonable and may lead to a useful and testable cell line for clinical studies.
- The proposed development candidate addresses a highly significant and unmet medical need, i.e. targeting patients with moderate to advanced PD who have become unresponsive to dopamine replacement therapy or other forms of treatment.
- The clinical competitiveness of the proposed therapeutic is excellent, given the dearth of treatment options for patients with advanced disease. While deep brain stimulation may be helpful for some, its high cost, risk of infection, variability, loss of efficacy and other associated challenges make cell therapy a more attractive option. If the proposed treatment proves effective and free of adverse events, this approach could become a routine procedure.
- The applicant describes a single development candidate and proposes activities that are fully within scope of this RFA.
Project Rationale and Feasibility
- The scientific rationale for dopaminergic cell replacement therapy in Parkinson’s Disease is very strong and based on several decades of preclinical and clinical research, including proof of principle that cell replacement theory can lead to clinically significant, long term improvements in PD patients.
- The proposed strategy for creating the candidate cell line is excellent. However, the application lacked sufficient preliminary data to convince reviewers that the resulting cells would lead to clinically successful neural transplants in PD patients. For example, there was scant evidence provided to validate the A9 identity of the MEF2C-programmed cells in vivo. Reviewers also questioned whether the observed neurite outgrowth would prove sufficiently robust to influence a target the size of a human striatum. Preliminary data to support meaningful neurite outgrowth, synapse with the host, and survival of human A9 neurons in the striatum would have significantly alleviated these concerns.
- The functional recovery described in the proposal did not compare favorably or prove better than that which has been observed historically for rodent or human tissue transplants. A more compelling case could be made with dose escalation studies, inclusion of additional behavioral assays, and a demonstration of long-term functional benefits and cell survival (i.e. beyond 8 weeks).
- The proposal does not include preclinical experiments to address long-term adverse effects such as dyskinesia, which have been observed in prior cell therapy studies for PD. In the absence of such data, the Food and Drug Administration (FDA) might impose significant restrictions on ensuing human studies. Reviewers recommended inclusion of such experiments and early engagement with the regulatory agency to discuss potential requirements.
- While the plan appears logical and feasible, some reviewers believed the timelines were overly optimistic, citing the challenges referred to above, and were not confident that an IND could be achieved in 4 years.
Principal Investigator (PI) and Planning Leader
- The PI exhibits a rare combination of excellence in both clinical neurology and basic science, with extensive experience developing therapies in a regulatory environment. S/he is highly qualified to lead this project.
- The consulting team includes several academic leaders in stem cell biology, neuroscience, neurology and neurosurgery. This group is highly experienced and will add considerable value to the project.
- The PI will serve as the Planning Leader and should have no trouble recruiting appropriate assistance and expertise if necessary.
- PROGRAMMATIC REVIEW
- A motion was made to move this application into Tier 1, Recommended for Funding, with a condition. 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. If the applicant anticipates that this condition cannot be met, the applicant may alternatively forfeit this Planning Award and enter the Early Translational Awards III competition at the Full Application stage to acquire more compelling preclinical data. The motion carried.