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Bone marrow and peripheral blood transplantation utilizing blood stem cells can provide curative treatment for patients with cancers and non-cancerous diseases of the blood and immune systems. Such treatments can be curative because the stem cells contained within the bone marrow or peripheral blood of healthy donors are capable of replacing the entirety of the patient’s blood system and providing a new immune system which can eradicate the patient’s cancer cells. The application of blood stem cell transplantation could be applied to a much larger population of patients if methods could be developed to expand blood stem cells in vitro or in vivo. This would be particularly beneficial for the broadened application of human cord blood transplantation for the many patients who lack an immune-matched sibling or unrelated donor. Furthermore, a method to expand human blood stem cells in vivo could be highly beneficial for the thousands of patients with cancer who require toxic chemotherapy which frequently results in decreased blood counts, infections and bleeding complications. A systemic treatment (i.e. a shot) which could cause blood stem cells to grow and produce more blood cells in patients could markedly improve patient’s outcomes after they receive such chemotherapy in the curative treatment of cancer. However, the development of treatments capable of inducing human blood stem cells to grow in the body has been very slow, in part due to a lack of understanding of the processes which govern blood stem cell growth in general. In my laboratory, we have developed mouse genetic models which allow us to discover new proteins produced in the bone marrow (the “soil” where blood stem cells reside) which make blood stem cells grow. We have recently discovered that 2 proteins are secreted by blood vessels within the bone marrow and cause blood stem cells to grow rapidly following damage with radiation. We are currently in the process of developing one of these into a growth factor that we can deliver to patients via injection as a means to cause their blood stem cells to grow after cord blood transplantation or following chemotherapy treatment for cancer. In this proposal, we will utilize our unique mouse models to discover the additional growth factors that make blood stem cells grow and we will perform pre-clinical studies to test whether these newly discovered growth factors can cause human blood stem cells to grow in vitro and in vivo. This proposal has the potential to generate new understanding of how human stem cells grow in vivo and to facilitate the development of new therapies which can regenerate human blood stem cells and the blood system as a whole in patients.
Statement of Benefit to California:
My research program has both basic science and pre-clinical components which I believe will benefit California in several important ways: First, my basic research program will contribute new fundamental knowledge in stem cell biology which will benefit students, fellows and faculty. My research will also synergize with other campus laboratories and other centers in California and will lead to collaborations and accelerated translation of these discoveries for regenerative medicine. Second, my research program has the potential to directly benefit patients in California. We have already discovered two niche-derived proteins which promote hematopoietic stem cell regeneration in vivo and are focusing substantial efforts now to develop these proteins as therapeutics for Phase I clinical trials. For example, we are developing one of the HSC regenerative factors which we discovered for a Phase I clinical trial to test its efficacy as a systemic therapy to accelerate cord blood engraftment and hematologic recovery in adult cord blood transplant patients. This has literal potential benefit for patients since approximately 10% of cord blood transplant patients die from complications of graft failure or delayed hematologic recovery. In addition, patients with cancer who receive myelosuppressive chemotherapy can potentially benefit from systemic administration of [REDACTED] or other HSC regenerative factors that we discover to accelerate hematologic recovery after chemotherapy. If we are able to show that administration of such regenerative factors can accelerate hematologic recovery in patients after chemotherapy, then remission rates for cancer patients may increase via more effective delivery of curative chemotherapy on time and to completion. Third, my research will provide new intellectual property. These inventions from my laboratory will be available for licensure to biotech or pharmaceutical companies in California. I have experience with licensing inventions from my laboratory to biotech companies and am eager to see my future inventions licensed to accelerate development for regenerative medicine. Fourth, my research program will provide new jobs and professional opportunities. At present, my research program provides partial or complete funding for more than 30 employees internally and more than 30 employees at our partner institutions in academia and biotechnology. I will also bring substantial federal research funding with me to California and will be hiring new fellows, technicians and faculty promptly upon my arrival. Taken together, I am hopeful that my research program will have a major benefit for the scientific community of California, for patients who may benefit from treatments we are developing, for the biotechnology community via the development of new intellectual property and for the larger economy via the creation of many new jobs. I sincerely look forward to the opportunity to bring my program to California.
Executive Summary The candidate principal investigator (PI) is a tenured physician-scientist and expert in the biology of hematopoietic stem cells (HSC) and their microenvironment. The proposed research falls within two broad areas, encompassing both basic and translational research objectives. In the first, the applicant plans to build on an existing pipeline of discovery to identify soluble factors that regulate self-renewal and survival of hematopoietic stem cells ex vivo, and to explore the molecular basis by which they do so. In the second, the applicant will perform preclinical studies with lead candidates identified through this pipeline, with the goal of developing clinically useful factors for expanding cord blood and improving the efficiency of HSC engraftment after transplantation. The applicant institution will provide support in the form of protected research time, laboratory space, matching funds, and access to intellectual and physical infrastructure in the basic and translational sciences. Research Vision and Plans - The key strength of this proposal is the applicant’s clear vision for translating his/her cutting edge discoveries to the clinic, which has been fostered by direct experience as both as a scientist and as a clinician. - The research plan builds logically on the applicant’s previous work, including a robust platform of discovery comprising unique tools, model systems, and a novel focus on the role of vascular factors in the regulation of blood stem cells. - The proposed research addresses current limitations to the application of HSC transplantation including graft failure, susceptibility to infection and low availability of donor cells. If successful, this research could lead to improved HSC transplantation procedures and potentially expand their therapeutic use into new areas. - The proposal is high risk due to its narrow focus on a lead candidate and the inherent challenges of translational research. Reviewers were confident, however, that some risk would be mitigated by continued generation of new lead candidates through the applicant’s robust discovery pipeline. - The proposal lacked a detailed discussion of potentially adverse effects that might occur with use of the HSC regenerative factors identified through this research, such as altered anti-viral or graft vs. tumor responses, development of autoimmunity, or promoting the growth/survival of malignant cells. It will be important to consider the influence of these factors on other blood cell types when assessing their perceived benefits. - While the experimental plans lacked detail, reviewers acknowledged the track record and continued productivity of the applicant PI in support of the project’s overall feasibility and potential. PI Accomplishments and Potential - The PI is a nationally recognized, accomplished physician-scientist who has made significant and impactful discoveries in the fields of hematopoietic stem cell biology and bone marrow transplantation. Reviewers described him/her has having introduced a “whole new dimension of investigation” to HSC biology. - The PI’s standing as a leader is evidenced by service on a number of national committees and editorial boards, including a recent appointment as chair of an important National Institute of Health (NIH) study session. - The application includes strong and enthusiastic letters of support from notable leaders in the field of hematology and regenerative medicine. Institutional Commitment and Environment - Institutional support is strong, comprising a generous start up package that includes matched funds, significant protected time for research, a large laboratory space, and access to world-class resources and infrastructure. - Reviewers were convinced that recruitment of the applicant would synergistically advance the clinical-translational efforts of his/her own research and that of the stem cell community at the applicant organization. - The environment at the applicant organization is outstanding for hematopoietic stem cell biology and has appropriate equipment and technical resources to support the initiation of clinical trials that may result from this program.