Funding opportunities

Executive Summary This proposal will assemble a team to perform imaging of hypoxic/ischemic injury in the brain of newborn animal models and study the potential use of stem cells (SCs) as a therapy for such lesions. The applicants will study the pathology of the brain and the behavioral outcome of cell therapy. At the same time they will use similar imaging parameters on newborn infants in order to select suitable patients prior to initiating clinical trials. The goal of this proposal is to use SCs to treat neonatal hypoxic-ischemic brain injury (HII). The applicant’s proposal is to induce ischemic lesions in rats, introduce SCs derived from a variety of sources, and track the cells in vivo using imaging techniques. In parallel, the applicant will correlate MRI findings in the animal model with observations from human newborn infants. Reviewers felt that the target is clearly identified by the applicants and plausible, and there is some published data supporting a therapeutic benefit of transplanted SCs in HII. However, while the clinical problem is highly relevant, the research approach in the present proposal is not sufficiently focused to achieve clinical readiness within 5 years. The applicant acknowledges that the best source of NSCs for repair of such lesions is not currently known and the team will undertake a large series of experiments to compare the results from many sources of transplantable cells, including human fetal, inducible pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and human embryonic stem cells (hESCs). This approach generates too many experiments and reviewers suggested that defining a specific source to carry forward should be done first. This application is largely an animal-model based proposal that is quite far from the clinic or the prospect of clinical translation. The problem/concept that this application is based on, is of extreme importance, however, this is a disease that may very likely not yet be ripe for a CIRM disease program funding. The Principal investigator (PI) has a long history of leadership within his/her own institution’s community and broadly within the fields of pediatric neurology and pediatric stroke. S/he has a solid publication record in the field in primarily specialty journals. The PI would appear to be well suited to lead the planning of the proposal and the team performing this work. S/he will rely heavily on another well known expert researcher for SC expertise. One reviewer noted that this expert is not physically close to the PI, which makes the collaboration less likely to occur on a frequent basis or as required by the project. The planning approach seems to have all the necessary elements and the applicant appears to have assembled an appropriate group of authorities in the fields of imaging, NSCs and experimental ischemia. However, one of the prevalent points of discussion by the reviewers was the fact that this overly ambitious plan will very likely not be ready for the clinic in 5 years. Reviewer One Comments Concept: Target: Neonatal hypoxic brain damage. Approval: use SCs (varying types, including neural stem cells (NSCs), etc) in animal models, image and follow neurobehaviour. The aim is to develop imaging methods that can be used to predict long-term outcome in neonates. The goal is to develop criteria for use of SCs for therapeutic purposes. This is largely an animal-model based proposal that is quite far from the clinic or the prospect of clinical translation. The problem is great but this is a disease that may very likely not be ripe yet for a CIRM disease program funding. Principal Investigator: The PI is chief of child neurology at PI’s institution medical school. He/She is an expert in imaging perinatal insults and an appropriate leader for the proposed effort. Planning Approach: The PI has assembled an excellent team of collaborators on aspects of NSCs, neonatology and imaging. Reviewer Two Comments Concept: Treatment for hypoxic-ischemic brain injury is an important potential application for SC therapies. The intent is to repopulate damaged areas of the brain with SCs capable of replenishing lost neurons and improving functional outcome. The target is clearly identified and plausible, and there is some published data supporting a therapeutic benefit of transplanted SCs. This proposal is a well-designed effort to use human data and animal models to determine whether there are benefits to SC therapy, how are they influenced by the SC source and by the severity of the brain injury. The strengths of this grant lie in the multiple SC sources and the very strong imaging applications that will be utilized to evaluate stroke severity and SC repopulation of damaged brain. In addition the proposal will establish criteria for stratification of potential recipients of SC therapy. The grant is clear and all the tools to complete these studies are in hand. A benefit of SC therapy in hypoxic-ischemic brain injury could be defined by this approach and result in a clinical trial within 5 years. Principal Investigator: The principal investigator (PI) is a well - recognized leader in pediatric stroke. He/She has a long history of leadership within his/her own institution community and broadly within the world of pediatric neurology and pediatric stroke. He/She has been involved in developing multiple consensus opinions in this area. Moreover, he/she has assembled a strong team that will be capable of applying stem cell biology, advanced imaging and the necessary analytical tools to evaluate the effects of stem cell interventions. There is little doubt that this team would be able to complete the proposed studies and develop a Disease Team Award application. Planning Approach: The planning approach has all necessary elements. A research team has been assembled to perform the necessary animal, retrospective and prospective clinical studies. There is an external advisory panel composed of additional leaders in this field and a clear plan for multidisciplinary meetings to review data and develop future plans. Reviewer Three Comments Concept: This proposal will deal with a clinically important problem. However, while the clinical problem is highly relevant, the research approach has the appearance of a fishing trip. They acknowledge that the best source of NSCs for repair of such lesions is not known and they will undertake a huge series of experiments to compare the results from many sources of transplants of cells. This might suggest that the first thing they need to do is define their source and then explore perhaps one or two sources of NSCs in a head-to-head comparison. Although they suggest that their research will lead to clinical trials in four years, this seems somewhat empirical. The idea of using iron particle labeling of the transplanted cells is not novel and there is quite solid evidence that this does not affect cell function after transplantation despite their concerns. Principal Investigator: The PI is a senior pediatrician and chair of the Department of Pediatrics. He/She has an R01 on a highly related imaging study in children with traumatic brain injury. He/She has a solid publication record in the field in primarily specialty journals. He/She clearly qualifies as an expert in the field. He/She would appear to be well suited to lead the planning of the proposal but will rely heavily on another well known and expert SC researcher for SC expertise (this expert is not physically close to the PI, which makes the collaboration less likely to occur in a frequent basis or as required by the project). Planning Approach: They appear to have assembled an appropriate group of authorities in the fields of imaging and experimental ischemia. However, they lack direct input in SC biology at the PI’s institution. The planning of the research to be proposed in the major grant application will take place at two meetings. Reviewer Four Comments Concept: The PI proposes to study neonatal hypoxic ischemic brain injury in rodent models and in humans through sophisticated, newly developed neuroimaging studies. The primary focus of these studies, which I believe are extremely important, will correlate findings modeled in the rats with observations observed in human newborn babies. In the human babies, follow-up at 18 months of age will be used to validate the predictive model of the neuroimaging techniques developed as part of these studies. Methods for stem cell labeling, tracking and engraftment will be developed and modeled in rat pups in preparation for human clinical trials. These are highly relevant studies which will have wide spread applicability in the study of other brain injuries in both children and adults. Principal Investigator: The PI is a distinguished professor of pediatrics and highly qualified to lead the team performing this work. His/Her extensive experience studying severe brain insults in children, effects of medical interventions in babies with hypoxic ischemic encephalopathy (HIE) and prognostic significance of magnetic resonance imaging (MRI) findings in newborns with HIE are all examples of the expertise he brings to this team. Planning Approach: The planning process is well designed and likely to succeed. These will be difficult clinical trials to conduct. The plan outlined appears to address the issues that need to be considered. The team proposed has the varied expertise to compete for subsequent awards.