This proposal describes a comprehensive career development plan for Dr. Kristin Page-Chartrand (PI), a faculty member in the Division of Pediatric Blood and Marrow Transplant Program at Duke University Medical Center. The long term career goal of the PI is to become an independent physician scientist conducting translational research in the fields of pediatric transplantation and regenerative medicine. Her current proposal focuses on studies that should result in improved engraftment and outcomes for children undergoing unrelated donor umbilical cord blood transplantation (UCBT). The environment for this candidate is outstanding, providing unique opportunities and resources to conduct her studies and to enhance her career development. Duke University Medical Center is a world renowned academic medical center with a long-standing track record in basic, translational and clinical research. Her mentor, Dr. Joanne Kurtzberg is a pioneer in the field of UCBT and cord blood (CB) banking. The advisory committee assembled is comprised of national and international experts in UCBT, biostatistics and clinical methodology with an established record of successfully mentoring clinician-scientists to highly productive research careers. In addition to expert mentoring, a comprehensive curriculum has been developed to enhance skills in clinical trial design and management, biostatistics, CB processing and testing. This proposal also draws on the strengths of resources at Duke University Medical Center readily available to the PI including the Pediatric and Adult transplant programs, the Carolinas Cord Blood Bank (CCBB), the Duke Stem Cell Laboratory, the Duke Translational Medicine Institute, the Duke Clinical Research Institute (DCRI), the DCRI Clinical Research Training Program, Aldagen Inc, and the EMMES Corporation. The research proposal focuses on strategies to improve outcomes of unrelated donor UCBT, a procedure that has improved overall access to transplantation. The major obstacle to the success of UCBT is primary graft failure, which occurs in up to 20% of patients. The central hypothesis of this proposal is that a significant portion of graft failure after UCBT is due to inadequate potency of some cord blood (CB) grafts that is not adequately assessed by current graft selection criteria (e.g. total nucleated cell count [TNC] and Human Leukocyte Antigen [HLA] matching). Currently, there are no standardized practices, validated tests or algorithms accepted by cord blood banks or transplant centers to select cord blood units (CBUs) for transplantation. Most importantly, the field lacks potency assays predictive of CB engraftment that could guide CBU selection for transplantation. Preliminary studies performed by the PI showed that colony forming units (CFUs), measured on the CB graft have the highest correlation with neutrophil engraftment after UCBT (p<0.0001), but this assay is lengthy and hard to standardize. Cellular expression of the enzyme aldehyde dehydrogenase (ALDH) is a marker of hematopoietic stem and progenitor cells that can be measured in a segment from a cryopreserved CBU and has a high correlation with CFU content in a CBU. In this proposal, Dr. Page-Chartrand will investigate whether the segment based ALDHbr assay can serve as a surrogate or as an adjunct to the CFU assay and also whether it can be incorporated into in the Cord Blood Apgar (CBA) described below, strengthening its predictive activity. The major goal of this proposal is to further validate a weighted scoring system named the Cord Blood Apgar (CBA) score. The CBA assigns three scores to a CBU based on pre-cryopreserved data (pre-cryo), post-thaw data, and a composite score based on combined pre-cryo and post-thaw data. The CBA was created and validated using a retrospective database of patients at a single institution receiving a single, non- manipulated CBU after myeloablative conditioning with the weighting based on the magnitude of the hazard ratios in univariate analysis of several graft characteristics. Preliminary work has been completed but a prospective validation is required before incorporating the CBA into clinical practice.
The specific aims are to: (1) to further validate the Cord Blood Apgar as an independent predictor of engraftment using an external, larger international registry database, (2) to determine whether ALDHbr content assayed on an attached segment can substituted for the CFU assay in determining CBU potency and determine the relationship between the segment and the product in the cryopreservation bag, and (3) to prospectively validate the CBA by studying units released for UCBT from the CCBB. If results from Aim 2 are favorable, further exploration into the impact of adding ALDHbr content to the CBA in these transplants is planned.
Umbilical cord blood transplantation is a life-saving therapy for patients with leukemia and other cancers, sickle cell anemia, bone marrow failure syndromes, immunodeficiency diseases and other rare genetic diseases. Cord blood donors do not have to match as closely as adult donors thus providing access to transplantation for many patients, particularly those of racial minorities, who will never find a fully matched donor. The major problem with cord blood transplantation is graft failure which can occur in as many as 1 in 5 patients. We think that some of this graft failure is due to damage caused to the cord blood unit during the processes of freezing, storage and thawing which might be detectable by testing the unit before it is released for a patient. We have created a scoring system for cord blood units that will allow doctors to choose the healthiest cord blood units that are most likely to result in successful transplant for their patients. We have also created tests that can be performed on a small test sample of the cord blood that may further improve the scoring system. The information learned from these studies will be combined to develop a strategy to select the healthiest cord blood unit for a patient which will increase the success of cord blood transplantation overall.
|Page, Kristin M; Mendizabal, Adam; Betz-Stablein, Brigid et al. (2014) Optimizing donor selection for public cord blood banking: influence of maternal, infant, and collection characteristics on cord blood unit quality. Transfusion 54:340-52|
|Page, Kristin M; Zhang, Lijun; Mendizabal, Adam et al. (2012) The Cord Blood Apgar: a novel scoring system to optimize selection of banked cord blood grafts for transplantation (CME). Transfusion 52:272-83|