Disease Team Therapy Planning I
Ongoing degeneration of dopaminergic (DA) neurons in the midbrain is the hallmark of Parkinson’s disease (PD), a movement disorder that manifests with tremor, bradykinesia and rigidity. One million Americans live with PD and 60,000 are diagnosed with this disease each year. Although the cost is $25 billion per year in the United States alone, existing therapies for PD are only palliative and treat the symptoms but do not address the underlying cause. Levodopa, the gold standard pharmacological treatment to restore dopamine, is compromised over time by decreased efficacy and particularly increased side effects over time. Neural transplantation is a promising strategy for improving dopaminergic dysfunction in PD. The rationale behind neural transplantation is that grafting cells that produce DA into the denervated striatum will reestablish regulated neurotransmission and restore function. Indeed, over 20 years of research using fetal mesencephalic tissue as a source of DA neurons has demonstrated the therapeutic potential of cell transplantation therapy in animal model of PD and in human patients. However, there are limitations associated with primary human fetal tissue transplantation, including high tissue variability, lack of scalability, ethical concerns and inability to obtain an epidemiologically meaningful quantity of tissue. Thus, the control of the identity, purity and potency of these cells becomes exceedingly difficult and jeopardizes both the safety of the patient and the efficacy of the therapy. Thus the search of self-renewable sources of cells is a very worthwhile goal with societal importance and commercial application. Human neural stem cells are currently the only potential reliable and continuous source of homogenous and qualified populations of DA neurons for cell therapy for PD. Such cell source is ideal for developing a consistently safe and efficacious cellular product for treating large number of PD patients in California and throughout the world We have developed a human neural stem cell line with midbrain dopaminergic properties and the technology to make 75% of the neuronal population express dopamine. We have also shown that these cells are efficacious in the most authentic animal model of PD. We now propose to conduct the manufacturing of these cells in conjunction with the safety and efficacy testing to bring this much needed cellular product to PD patients and treat this devastating disease.
Statement of Benefit to California:
In this grant application we propose to develop a unique technology to manufacture neurons that will be used to treat patients suffering from Parkinson’s disease. One million Americans live with PD and 60,000 are diagnosed with this disease each year. Although the cost is $25 billion per year in the United States alone, existing therapies for PD are only palliative and treat the symptoms but do not address the underlying cause. Levodopa, the gold standard pharmacological treatment to restore dopamine, is compromised over time by decreased efficacy and increased side effects. Human stem cells are currently the only potential reliable and continuous source of homogenous and qualified populations of DA neurons for cell therapy for PD. Such cell source is ideal for developing a consistently safe and efficacious cellular product for treating large number of PD patients in California and throughout the world We have developed a human neural stem cell line with midbrain dopaminergic properties and the technology to make 75% of the neuronal population express dopamine. We have also shown that these cells are efficacious in the most authentic animal model of PD. We now propose to conduct the manufacturing of these cells and safety and efficacy testing to bring this cell product to PD patients and treat this devastating disease. The CIRM grant will help us create further intellectual property pertaining to the optimization of the process of manufacturing of the cellular product we developed to treat PD. The grant will also create jobs at Californian institutions and contract companies we will work with to develop this product. Importantly, the intellectual property will be made available for licensing to biotechnology companies here in California to develop this product to treat the over 10 million people afflicted with PD world wide. Revenues from such a product will be beneficial to the California economy.
EXECUTIVE SUMMARY Project synopsis The applicant’s objective is to develop a stem cell therapeutic for the treatment of Parkinson’s disease (PD). The proposed product consists of undifferentiated human neural stem cells (hNSCs) from a line that displays an in vitro differentiation potential consistent with the A9 dopaminergic neuronal phenotype, the cell type lost in PD. The hNSCs will be delivered directly into relevant brain regions, and are expected to differentiate into A9 neurons in vivo. The goal is to acquire the necessary data for filing an investigational new drug (IND) application by the end of the research project. Significance and Impact - The effective treatment of PD represents a clear unmet medical need. Current treatment with L-dopa eventually fails and produces significant disabling side effects. Similarly, deep brain stimulation displays limited benefit, requires a high level of expertise, and adverse events are common. Novel therapies are in development including growth factors and gene therapy but all have limitations in large part due to the blood brain barrier. Thus, there is a clear need for the development of cell-based therapies, which have the potential to yield desired effects with a single operation. - If the proposed treatment were to prove successful, it has the potential to eventually have a major impact on the health and well being of PD patients. It is extremely unlikely it will alleviate all symptoms, but could prove to be a major advance. - The applicants describe a single development candidate that meets the criteria for an eligible cell type for this RFA, and propose appropriate IND-enabling studies. Project Rationale and Feasibility - Previous studies with tissue transplants in humans provide a strong rationale for cell-based therapy in PD. The applicant provides further proof of concept with an hNSC transplant study in a standard PD animal model, showing cell engraftment and improved behavioral function. - Reviewers supported the ultimate goal of providing properly integrated and functioning A9 neurons (in this case via hNSC transplantation) as a valid concept for cell replacement therapy for PD. - The applicant does not discuss neurite outgrowth from transplanted hNSC-derived cells, and no evidence for outgrowth from the graft into the animal model’s striatum is provided. Furthermore, the cited published study does not show robust tyrosine hydroxylase (TH) terminals throughout the striatum several mm from the graft. It would be critical to include such data in the research grant application. - No evidence of robust in vivo cell survival is provided, although reviewers acknowledged such data may have been present but were truncated due to exceeding the page limit. - The applicant points to published data showing behavioral improvement in a PD animal model, but these data may have been generated using a different hNSC cell line than the one proposed. The applicant is not an author on that paper and cell line names are not clearly stated in these studies. - It appears the intention is to derive a good manufacturing practice (GMP) grade line from the existing research grade hNSC line. This is not straightforward and in the event that it is not possible, the proposed studies would be jeopardized. - The applicant did not specify what stage of PD would be targeted in the clinical study. - The IND-enabling studies as proposed were considered to be reasonably feasible. However, success will depend on whether further efficacy studies and histological analyses requested by the reviewers (see programmatic review) turn out to support the existing data. The design and completion of a valid tumorigenicity study presents another unknown. Principal Investigator (PI) and Planning Leader - The leadership team is first rate both scientifically and clinically. - Both the Principal Investigator (PI) and the Planning Leader (PL) have significant experience and insight into translational issues. - The PI has filed 3 IND applications for cell and gene therapy including one in PD and is thus well qualified to lead this effort. - The PL is a well-known clinician and investigator in PD research and has leadership experience; the PL is thus well suited to organize the proposed project team.
- 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 hNSC-derived A9 dopaminergic neurons in the striatum, with histological data showing robust neurite outgrowth (3-5 mm from the graft, volumetric evaluation) and synaptic connections with the host brain. These data should be with the hNSC line intended for use in clinical trials. 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.