Early Translational III
The goal of this project is to produce a stem cell-based therapy for stroke (also known as an ischemic cerebral infarct). Stroke is the third leading cause of death in the USA, and a leading cause of disability among adults. Currently, there are no effective treatments once a stroke has occurred (termed completed stroke). In this proposal, we aim to develop human stem cells for therapeutic transplantation to treat stroke. Potential benefits will outweigh risks because only patients with severe strokes that have compromised activities of daily living to an extreme degree will initially be treated. Currently, there are no effective treatments once a stroke has occurred. In this proposal we will develop human stem cells for therapeutic transplantation to treat stroke. Using a novel approach, we will generate stem cells that do not form tumors, but instead only make new nerve cells. We will give drugs to avoid rejection of the transplanted cells. Thus, the treatment should be safe. We will first test the cells in stroke models in rodents (mice and rats) in preparation for a human clinical trial. We will collect a great deal of data on the mice and rats to determine if the stem cells indeed become new nerve to replace the damaged tissue and to assess if the behavior of the mice and rats has improved. If successfully developed and commercialized, this approach has the potential for revolutionizing stroke therapy.
Statement of Benefit to California:
Stroke (cerebral ischemia) is the third leading cause of death in California, and a leading cause of disability among adults. Currently, there are no effective treatments once a stroke has occurred. Hence, many Californians are affected by stroke and because of this can no longer work, socialize with their family or friends, or enjoy life. The profound effect on family members of a stroke victim is also not to be minimized, since they must change their own life in order to care for their loved one who has suffered a stroke. Moreover, even Californians in families who have not suffered from a stroke are affected because they are directly or indirectly paying for the care of stroke victims who end up on welfare. Hence, both the human and economic burden of stroke is tremendous. In this proposal we aim to develop human stem cells for therapeutic transplantation to treat stroke patients. With such therapy we feel that we can improve the plight of stroke victims. We also believe that an effective, straightforward, and broadly understandable way to describe the benefits of this proposal to the citizens of California is to couch the work in the business concept of “Return on Investment.” Not only the novel therapy for stroke that will be developed as a result of our research program will provide direct benefits to the health of California citizens, but also this program will generate potentially tangible monetary benefits to the citizens of California.
This application for a Development Candidate Award is focused on a human embryonic stem cell (hESC)-derived neural progenitor cell (NPC) therapy for stroke. The applicant proposes to transiently genetically modify NPCs to improve survival and differentiation into neurons following transplant into the stroke brain. There are four milestones proposed: 1) to transduce hESC-derived NPCs with a viral vector and verify neurogenesis in vitro; 2) to transplant these NPCs into animal models of stroke; 3) to analyze these animals to verify neuronal differentiation and integration in vivo; and 4) to analyze the behavior of these animals to determine if the NPCs ameliorate stroke-induced deficits. Objective and Milestones - It is not clear that this project will be ready to advance into IND-enabling studies in three years. The proposal is premature for a Development Candidate Award and would be better suited for a Development Candidate Feasibility Award. - The Target Product Profile (TPP) mixes clinical information with preclinical animal studies. The TPP should describe desired clinical attributes of the proposed therapeutic. In addition, the desired safety profile should be specific to the proposed product without referencing other products. Rationale and Significance - Stroke causes irreversible damage to the brain and there are currently few effective treatments. Any stem cell based restoration of the central nervous system would be a major advancement in stroke therapy. - The choice of patient population is not well justified. Reviewers noted that the proposed treatment window post-stroke is too early to assess the patient’s likelihood of improvement. They suggested a later time point that would allow for patient stabilization and stratification. Research Project Feasibility and Design - Very large numbers of animals are proposed in the budget section, which are not feasible over the course of a three year award. That these very large numbers are required to achieve statistical significance suggests that the biological effect of NPC transplant in animal models of stroke is very small. - The applicant proposes that the viral vector will result in transient gene expression but does not propose experiments to confirm this hypothesis. Vector expression may be diluted in dividing NPCs or may persist in postmitotic neurons. In addition, no data are provided regarding the efficiency of gene expression using this vector in NPCs. - The preliminary data demonstrating NPC differentiation and integration following transplant is encouraging. The functional improvement in an animal model of stroke is modest but statistically significant. - The research plan does not include a thorough investigation of safety endpoints. In particular, the potential for newly transplanted neurons to cause abnormal activity and seizures should be examined. - The robust animal studies do not include a significant effort to optimize the cell transplantation and dosing regimens. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI has a strong track record in neuroscience research. However, the team does not appear to have much experience in product development. - The proposed budget is considerable and the very large number of animals is not justified. Collaborations, Assets, Resources and Environment No relevant concerns were highlighted by reviewers under this review criterion. Responsiveness to the RFA - This application is responsive to the RFA. It proposes hESC-derived NPCs for stroke. CIRM’s translational portfolio includes one Disease Team award for stroke.
- A motion was made to move this application into Tier 3, Not Recommended for Funding. The motion carried.