Early Translational III
Stroke is the leading cause of adult disability, with an estimated 795,000 new strokes per year and almost 1/3 of stroke patients requiring long-term institutional care. Stroke causes disability because of the brain’s limited ability to repair. There are no therapies that promote recovery of function in stroke. Recent studies indicate that stem cell therapies in stroke promote better recovery. These studies are limited by the use of stem cell types that are not specific for the area of brain damage in stroke and the delivery of cells in a generic suspension of fluid. This research project develops a new stem cell therapy for stroke that is specific for the damaged brain region, and uses a delivery system that promotes cell interactions and conforms to the geometry of the damaged area. This project is novel in the stroke field in two ways. First, it uses emerging laboratory techniques to differentiate induced pluripotent stem cells into a brain-region specific cell type. This cell type is more likely to survive and repair in the damaged area and, because it is no longer immature, is less likely to form tumors. Second, this project uses bioengineering to develop a novel sheet of stem/progenitor cells for brain transplantation after stroke. This sheet preserves the cellular interactions that are crucial for stem cell survival and conforms to the geometry of the target brain region, cerebral cortex, to make for a minimally invasive delivery approach.
Statement of Benefit to California:
Stroke is a significant medical problem in California. In the United States, stroke is the leading cause of disability. In California, 1 in 10 Californians have been diagnosed with a stroke and stroke accounts for 1 in 20 hospital discharges. The rate of death after stroke is declining, but the incidence of stroke is increasing. These trends are occurring because better early hospital care prevents stroke deaths, but the aging of the population means that more people are getting strokes. These two trends mean that there will be ever more disabled stroke survivors in California in future years. The studies in this research program develop a new stem cell therapy to promote recovery in stroke. This program goes after an unmet clinical need, as there is no therapy that promotes recovery of function in stroke. This program uses advanced stem cell biology and tissue bioengineering to develop stem cells that are specific for the brain region most commonly damaged in stroke, and a delivery system that is minimally invasive and targets the unique structure of the damaged brain region.
This application for a Development Candidate Feasibility Award focuses on a tissue-engineered, induced pluripotent stem cell (iPSC) derived therapy for stroke. The applicant proposes to develop a sheet of iPSC-derived cortical motor neurons to transplant into the stroke-injured brain. There are three milestones proposed: 1) to establish optimal conditions to derive cortical motor neurons from iPSCs; 2) to develop a transplantation protocol for these cells in animal models of stroke; and 3) to generate tissue-engineered sheets of these cells and test them in animal models of stroke. Objective and Milestones - Most of the described milestones involve exploratory or basic research questions. It seems unlikely that a candidate for further preclinical development will emerge during the funding period given the large number of variables to be tested prior to initiating studies with the proposed development candidate. - It is unclear why the development of cortical motor neuron sheets is delayed until the end of the project period, given that this construct is the basis of the proposal’s rationale and novelty. - The proposed route of cell transplantation is not clear, as different routes are described in the Target Product Profile and Milestone 3 of the research plan. - It is not clear how results obtained in Milestone 2 will inform experiments in Milestone 3 using a completely different cell formulation. Rationale and Significance - The scientific rationale for the transplantation of cortical motor neuron sheets is not well justified. It is not clear how the transplantation location proposed in Milestone 3 would permit restoration of motor circuitry. - Stroke is a leading cause of disability and few treatment options are currently available. Interventions that could restore function, even to a limited extent, would be significant. Research Project Feasibility and Design - Milestone 1 may not be feasible in the proposed time frame. Manipulation of each proposed variable and subsequent evaluation of efficacy will not allow sufficient time to consider the combination strategies likely to be necessary. Reviewers noted that the inclusion of a go/no-go decision tree to illustrate the optimization plan would have been helpful. - The preliminary data are not sufficient to support the therapeutic approach. The level of purity of cortical motor neurons achieved thus far may not be sufficient and the development of sheets of these cells is at an early stage. In addition, the cells used in the preliminary functional outcome study are different than the proposed cells. - A major limitation in the research plan is that immunosuppression is left out of the experimental design matrix. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The research team is excellent and the PI and Partner PI bring synergistic expertise to the project. - The PI has an extensive track record of excellence in the field of neurological injury and cell therapy. S/he is also a prototype for excellence in training as a clinician-scientist. - The Partner PI has expertise in iPSC differentiation and transplantation and has developed bioengineering methodologies that are critical to the proposed work. Collaborations, Assets, Resources and Environment - The collaborative team combines two investigators with unique skill sets, which is a strength of the proposal. - Regular communication between the two PIs is planned and web-based infrastructure will be put in place to track planning and progress. - Reviewers suggested that it would be useful to understand how the potential roadblock of IP transfer between the PI institutions would be addressed. Responsiveness to the RFA - The proposal is responsive to the RFA. Human iPSCs are necessary to achieve the outcomes of the study.