Stroke is the leading cause of adult disability. Most patients survive their initial stroke, but do not recover fully. Because of incomplete recovery, up to 1/3 of stroke patients are taken from independence to a nursing home or assisted living environment, and most are left with some disability in strength or control of the arms or legs. There is no treatment that promotes brain repair and recovery in this disease. Recent studies have shown that stem cell transplantation into the brain can promote repair and recovery in animal models of stroke. However, a stem cell therapy for stroke has not reached the clinic. There are at least three limitations to the development of a human stroke stem cell therapy: most of the transplanted cells die, most of the cells that survive do not interact with the surrounding brain, and the process of injecting stem cells into the brain may damage the normal brain tissue that is near the stroke site. The studies in this grant develop a novel investigative team and research approach to achieve a solution to these limits. Using the combined expertise of engineering, stem cell biology and stroke scientists the studies in this grant will develop tissue bioengineering systems for a stem cell therapy in stroke. The studies will develop a biopolymer hydrogel that provides a pro-growth and pro-survival environment for stem cells when injected with them into the brain. This approach has three unique aspects. First, the hydrogel system utilizes biological components that mimic the normal brain environment and releases specific growth factors that enhance transplanted stem cell survival. Second, these growth factors will also likely stimulate the normal brain to undergo repair and recovery, providing a dual mechanism for neural repair after stroke. Third, this approach allows targeting of the stroke cavity for a stem cell transplant, and not normal brain. The stroke cavity is an ideal target for a stroke stem cell therapy, as it is a cavity and can receive a stem cell transplant without displacing normal brain, and it lies adjacent to the site in the brain of most recovery in this disease—placing the stem cell transplant near the target brain region for repair in stroke.
The progress from stroke stem cell research has identified stem cell transplantation as a promising treatment for stroke. The research in this grant develops a next generation in stem cell therapies for the brain by combining new bioengineering techniques to develop an integrated hydrogel/stem cell system for transplantation, survival and neural repair in this disease.
Advances in the early treatment of stroke have led to a decline in the death rate from this disease. At the same time, the overall incidence of stroke is projected to substantially increase because of the aging population. These two facts mean that stroke will not be lethal, but instead produce a greater number of disabled survivors. A 2006 estimate placed over half of the annual cost in stroke as committed to disabled stroke survivors, and exceeding $30 billion per year in the United States. The studies in this grant develop a novel stem cell therapy in stroke by focusing on one major bottleneck in this disease: the inability of most stem cell therapies to survive and repair the injured brain. With its large population California accounts for roughly 24% of all stroke hospital discharges in the Unites States. The development of a new stem cell therapy approach for this disease will lead to a direct benefit to the State of California.
This application is focused on the development of a novel hydrogel to support neural progenitor cell (NPC) survival following transplantation to treat stroke. The translational bottleneck addressed is the limited survival, differentiation and integration of transplanted stem and progenitor cells in preclinical stroke models. A novel hydrogel/NPC system could serve multiple therapeutic purposes by allowing injection of NPCs directly into the stroke cavity, supporting transplanted NPC survival and enhancing endogenous repair mechanisms. The applicant proposes to develop this system in four Specific Aims: (1) to generate two subtypes of NPCs from human induced pluripotent stem cells (iPSCs); (2) to synthesize novel hydrogel candidates by systematically modifying three components; (3) to culture these hydrogels with iPSC-derived NPCs and assess cell proliferation, organization and differentiation; and (4) to test the optimal hydrogel in combination with NPCs in a mouse model of stroke.
Reviewers agreed that this proposal addresses a significant bottleneck in translational stem cell research. Stroke is a prevalent disease with few treatment options and any improvements in cell transplantation strategies could have a major impact. The cavity that results from cell death following stroke is inhospitable to transplanted cells and so engineering a matrix to enhance cell survival would be an important advance. Reviewers found the proposal’s approach to be fairly innovative and its scientific rationale sound.
The reviewers described the research plan as complex but carefully designed and feasible. They appreciated that strong preliminary data are presented for each specific aim. Reviewers agreed that the experimental design addresses a number of issues that must be resolved before stem cell transplantation for stroke can be successfully translated to the clinic, including identification of the appropriate NPC population and method of delivery. They described the in vivo testing in Aim 4 as a strength, although they recommended a greater number of functional assays in order to validate the approach. Reviewers did raise a number of minor concerns, many related to the complexity of the final product proposed. They noted that this complexity may pose significant barriers to translation and commercialization. In addition, they cautioned that the large number of components to be varied in the hydrogel/NPC constructs may make interpretation of the in vivo data difficult. One reviewer noted that the proposed extracellular matrix tripeptide has significantly less potency and specificity than hexapeptides and cyclic peptides and recommended that slightly longer peptides be considered for gel modification. Finally, the reviewers noted that while pitfalls are acknowledged throughout the proposal, clear alternative plans are not presented.
Reviewers praised the excellent research team, which has significant expertise in each of the three areas of the proposal: iPSCs, biomaterials and animal models of stroke. They noted that the Principal Investigator has a good track record in stroke research and is an emerging leader in the field. Reviewers did note that the research team is quite large and may be difficult to keep focused. Given the high number of FTEs they found the supply budget to be inadequate. They also weren’t sure why the animal budget is expected to decrease over time, given that materials development will occur early in the grant and animal studies later.
Overall, reviewers were supportive of this proposal to address a significant bottleneck to the translation of stem cell therapies for stroke. While they raised concerns about the complexity of the research plan, the reviewers were ultimately convinced of its feasibility by the strong preliminary data and excellent research team.
- A motion was made to move this application into Tier 1, Recommended for Funding. A Grants Working Group member noted that while CIRM has some stroke funding in its portfolio, the disease is underrepresented relative to the severity and prevalence of the disease. The motion carried.