Disease Team Planning
Stroke is the leading cause of adult disability. As Californians adopt health measures that minimize stroke risk factors, such as high blood pressure and smoking, the number one risk factor for stroke cannot be controlled: age. As the population ages the incidence of stroke is expected to markedly increase to almost 1.2 million cases per year in the United States, with a disproportionate increase in stroke in California with its relative population growth in older age groups. Because most of the cost in stroke is in the chronic care of disabled survivors, studies indicate that this increase in stroke incidence may cause the total cost of caring for stroke victims in the next quarter century in the United States to top $1 trillion dollars. Stroke induces a limited degree of functional recovery. In humans, this recovery is associated with functional re-organization of the tissue adjacent to the stroke site. Recent studies have shown that stem cell transplantation enhances functional recovery in animal models of stroke. However, these stem cell therapies in animal models of stroke have not translated into new clinical therapies for several important reasons. First, most studies have transplanted stem cells into normal brain that is adjacent to the stroke site. Because cell transplantation produces a degree of damage, this approach disrupts the very brain tissue that participates in normal functional recovery in humans. Second, most of the transplanted cells die after transplantation, a process termed “transplant shock”. Third, the mechanisms of recovery in experimental animal models of stroke, such as mice, have been difficult to generalize to the larger and more complex human brain. This grant assembles a team of clinicians and basic scientists that will apply emerging biomedical technologies to transplant stem cells directly into the stroke tissue and not normal brain, enhance the survival of these cells, and measure their effects on functional recovery using behavioral tests and advanced brain imaging modalities that can be applied to human stroke stem cell trials. This team involves scientists that range from bioengineers, stem cell and neuro-biologists to neurosurgeons and stroke and neurorehabilitation clinicians. The team is organized to facilitate communication among these disciplines so that its novel technologies, such as an injectable biological matrix that promotes stem cell survival, are developed in a clinically relevant way for application to human therapies at the completion of the grant period. Stroke takes up to one-third of patients from independence to a nursing home or other institution and renders over one-half of patients unable to walk without assistance. This grant focuses on the development of a clinically ready stem cell therapy to promote recovery in this devastating disease.
Statement of Benefit to California:
The proposed research will identify a treatment that promotes functional recovery after stroke. Stroke is the leading cause of adult disability. There are no current treatments that stimulate brain repair and recovery in this disease. The research in this grant will assemble a team and a treatment process that uses new technologies to develop a stem cell-based therapy for neural repair after stroke.
Executive Summary This proposal is designed to put in place a team to focus on stem/progenitor cell transplantation approaches to treat stroke, and specifically, to directly target ischemic brain tissue while sparing normal brain. The goal of this work is to try to enhance cell survival within ischemic tissue by creating novel microenvironments that support transplant survival and neural repair. The applicant proposes to explore novel technologies to deliver the cells directly and selectively into the stroke tissue, enhance survival of the cells, and measure effects on functional recovery by novel imaging and behavioral outcome measures. Based on preclinical data, the applicant and proposed team plan to quickly move toward the clinic with appropriate regulatory and compliance using good manufacturing practice (GMP) banked cell lines. Reviewers recognized that stroke is a leading cause of adult disability and is a largely unmet clinical need. Although cell based therapies have proven fairly ineffective in preclinical models to date, the goal of this work is to try to support cell survival within the ischemic environment by creating novel microenvironments that support transplant survival and neural repair. The development of new therapeutic approaches for brain repair and neuroprotection in stroke patients would be extremely important. This is a very significant problem in a mature field that will likely be addressed by cell therapy. Reviewers felt that the PI is a well established stroke physician and neuroscientist, who has assembled a team of prominent, internationally recognized experts in the fields of neurobiology and transplantation. Moreover, the PI has already led several large program grants in this field and, together with the team that s/he has assembled, should be able to see this work through fruition. One reviewer commented that the PI has the ability to lead the effort and is likely an emerging clinician/scientist leader in stroke treatment. This proposal is well-written, concise, and has a clear pathway from preclinical development of cell delivery with good preclinical behavioral outcomes through to clinical translation using GMP banked neural stem cells (NSCs). The planning process will mainly consist of identifying the projects to be performed. The applicant will organize a series of meetings to plan the proposed studies. The review panel discussed two limitations in this submission. The panel felt it was unclear how the cells would be generated, and what the phenotype of the cells to be transplanted would be. Moreover, although the applicant stresses the novelty of the biopolymer hydrogel to be used to enhance cell survival, few details are provided in support of this technology. In summary, the PI has assembled an impressive group of neurobiologists and stem cell transplantation experts and, together with their novel technologies to deliver cells, this might lead to substantial improvements in cell based therapy for stroke within the 5 years timeframe required by this RFA. Reviewer One Comments Concept: This proposal addresses the therapeutic application of stem cells for the treatment of cerebrovascular disease. Stroke is a leading cause of adult disability and is a largely unmet clinical need. To date, cell based therapies have proved, in preclinical models, fairly ineffective. However the goal of this work is to try to support cell survival within the ischemic environment by creating novel microenvironments that support transplant survival and neural repair. This proposal is nicely written, concise, and has a clear pathway from preclinical development of cell delivery with good preclinical behavioral outcomes through to clinical translation using GMP banked neural SCs. One major limitation in this application is the lack of specificity regarding how the cells would be generated and the phenotype of cells to be transplanted. Moreover although the applicant stresses the novelty of the growth-factor impregnated biopolymer to be used to enhance cell survival, few details are provided in support of this. PI: The PI is a well established stroke physician and neuroscientist, although not a world leader in this field. He has assembled a team of prominent internationally recognized experts in the field of neurobiology and SC transplantation. He has led several large program grants in this field, and together with the team that he has assembled should be able to see this work through fruition. Planning Approach: The P.I. has put together a well laid out structured protocol for the use of cell therapy for the treatment of cerebrovascular disease. They propose to use human ES cell derived cell populations, although it is unclear in the proposal exactly how these cells will be generated and exactly what the phenotype of these cells will be. Nevertheless the P.I has assembled an impressive grouping of neurobiologists and SC transplantation experts, and together with their novel polymer bio-delivery system, this might lead to substantial improvements in cell based therapy for stroke therapy. Reviewer Two Comments Concept: This proposal deals with stroke, a major neurological problem in this country that has huge social and economic consequences. Hence new therapeutic approaches for brain repair and neuroprotection in stroke patients would be extremely important. The applicant identifies problems that have existed to date on applying transplant approaches in experimental models of ischemia. The concept that s/he presents here are the ways to surmount these problems in appropriate animal models where the therapy and outcome measures might more accurately represent what happens in patients with stroke. He will transplant cells directly into lesions to avoid damaging local tissues, and the cells used will be embedded in a supportive gel and engineered to express molecules that would help their survival. At the same time they would image the lesions and identify cells that have been labeled with nanoparticles. PI: The applicant is a practicing clinical neurologist who carries out basic and translational ischemia research at UCLA. He is extremely well funded, with 2 R01s and a major foundation grant. Another grant from the Adelson Foundation is mentioned in the text but not cited in his Biosketch. He has a pretty good publication record. As stated he already works with the key people who he will collaborate with at UCLA. I think he has the ability to lead the effort and is likely an emerging clinician/scientist leader in stroke treatment. Planning Approach: The planning process will mainly consist of identifying the projects to be performed if they are funded by the major grant along with the generation of some preliminary data that they need (described as budget justification). They plan a series of meetings to plan the proposed studies. This is not detailed in this section of the grant application and only noted in the budget justification. This might be the only weakness in this submission which otherwise is clearly and well written and exactly addresses the questions asked in the RFA.