Executive Summary The focus of the proposal is the development of a small molecule for ex vivo expansion of peripheral blood and cord blood hematopoietic stem cells (HSC) for use in various clinical settings including immunodeficiency states, autoimmune and hematopoietic diseases, and following high dose chemotherapy or radiation. The principal investigator (PI) has identified a small molecule that may have this expansion capability. A group of collaborators from the academic institution and industry has been assembled to plan and carry out experiments leading to clinical trials. Reviewers concurred that the ability to expand hematopoietic stem cells ex vivo would greatly enhance the efficacy of cord blood transplantation and other HSC transplantation protocols without increasing the risk of graft versus host disease (GVHD). While the proposed concept is potentially significant, the reviewers’ enthusiasm was limited by the weaknesses of the proposal. Sufficient evidence that the degree of expansion could be achieved was absent from the proposal, making it difficult to assess the maturity of the project. Moreover, no information on toxicity or toxicology studies is presented. Reviewers were also concerned about the lack of a disease focus as no specific disease target has been identified in the proposal. The PI was viewed as a strength of the application, noting his/her relevant experience in the hematopoietic stem cell field. He/She has worked in the biopharmacetical industry and has participated in developing novel therapies for the treatment of immune disorders and is thus well qualified to lead a multidisciplinary project team. The PI has identified and contacted several consultants and collaborators with expertise in hematopoietic cell transplantation, immunotherapy, hematopoietic cell expansion and differentiation. The planning approach seems reasonable, although the list of collaborators is relatively short, considering the broad range of studies needed. One reviewer expressed concern that the institutional support may be an issue for this potential project, as stem cell biology is not a current focus, and the application states that the institution does not currently have the capacity to run clinical trials. In summary the panel did not recommend this application for funding because of the limited evidence presented of the small molecule’s expansion capability, and the lack of a specific disease target. Reviewer One Comments Concept: PI: Michael Cooke Institution: Genomics Institute (Novartis) Disease Target: HSC expansion for autologous/allogeneic transplantation Concept: High-throughput screen has identified small molecules that appear to regulate self-renewal. Proposal is to develop this compound for clinical applications, one option is to expand cord blood progenitors where clinical utility is currently limited by insufficient cell dose. Strengths: 1. Good group of consultants/subcontractors. Mix of academic and industry 2. Preliminary data suggests a 10-fold increase over 14 days (compared to control, not to starting material?). 3. Novartis institute has a focus on multidisciplinary teams. Weaknesses: 1. No specific disease focus, all situations where HSCT is currently employed would be potential targets 2. Emphasis is on novel compound, not on cells. 3. PI is not a recognized leader in this field. 4. Target cells are not excluded from federal funds. 5. Correlation of HSC dose with engraftment time is minimal (small differences in time with very large differences in dose). 6. No other research support indicated? 7. Minimal details on planning approach. 8. Minimal details on team members roles 9. Stated that stem cells expansion is not a focus of Novartis. a. Stated that they do not have the capacity to run clinical trials. Principal Investigator: PI: Director of Gene Discovery at SyStemix for 5 years Planning Approach: 1. Consultants to travel for one day conference. 2. Biweekly teleconferences 3. Website Reviewer Two Comments Concept: The ability to expand hematopoietic stem cells ex vivo would greatly enhance the efficacy of cord blood transplantation and other HSC transplantation protocols without increasing the risk of GVHD. The investigators have identified a compound that may have this capacity, as it apparently increases the number of CD34 cells ten-fold in culture, increases CAFC numbers 9-fold and in a preliminary study led to increased engrafting ability in a NOD-SCID repopulation assay. These data are not presented, making the actual level of stem cell expansion difficult to assess. No information on toxicity or toxicology studies is presented. Moreover, a disease focus does not seem to have been identified. Thus, while an area of high significance has been identified and the rationale is clear, the compound is quite early in its development. Principal Investigator: Dr. Cooke has strong experience in the hematopoietic stem cell field, having been Director of Gene Discovery at SyStemix from 1994 to 1999. He became familiar with clinical, regulatory and business aspects of bringing HSC-based therapies into the clinic during that period. In 1999, he joined the newly established Genomics Institute of the Novartis Research Foundation, a multidisciplinary research institute where he serves as Director of Immunology. Dr. Cooke’s experience as part of a global project team to develop novel therapies to treat immune disorders and his participation in numerous interdisciplinary teams, several of which have successfully advanced novel therapeutics into clinical testing, positions him well to bring new compounds into clinical trials. Planning Approach: Dr. Cooke has identified and contacted several consultants and collaborators with expertise in hematopoietic cell transplantation, immunotherapy, hematopoietic cell expansion and differentiation. This includes Kenneth Kaushansky, Bruce Torbett, Ram Mandalam, Tom Lane and Ted Ball. Because Novartis does not currently have a stem cell-based therapy business focus, the trials will require a team approach. The team would be assembled by networking with leaders locally and nationally, by email, and teleconferences. An initial face-to-face meeting will be organized and experiments will be outlined, including pharmacology, toxicology, and analytical chemistry and cell biology. Decisions for what institutions can perform each type of study, what licenses will be needed, etc., will be determined. The planning and approach seem reasonable, although the list of collaborators is relatively short, considering the broad range of studies needed.