Published results of our accomplishments toward the goals of this project in the past fiscal year include: 1. Studies of the generation of induced pluripotent stem cells and gene correction of iPSC: A major accomplishment of our iPSC program over the past year and a half has been the development of an efficient method for genetically correct the CGD defect for all 5 forms of CGD in iPSC from patients with each of the 5 forms of CGD (Merling RK, et al. Mol Ther 2015, 23:147-57). This work has great potential for developing future treatments for CGD, including the generation of autologous gene corrected neutrophils derived from CGD to help control severe infections in patients with CGD that are not responding to conventional therapy. We have established a collaboration with Dr. David Stroncek in the Department of Transfusion Medicine, CC, NIH to establish GMP conditions for generating and maintaining iPSC. This is an important element of the long term goal of developing new treatments for CGD and X-SCID using autologous iPSC. A second major accomplish with our iPSC program is our work with collaborators in the FDA who have developed a proteome analysis method that has identified protein markers that define the quality of iPSC (Pripuzova NS, et al. Stem Cell Res 2015, 14:323-38). We have also published methods of efficient production of mature differentiated blood neutrophils from iPS cells (Sweeney CL, et al, Methods Mol Biol 2014, 1124:189-206 ). 2. Studies of the CXCR4 receptor and its importance in trafficking of HSC and other types of blood cells: We have worked closely with our colleagues in the Murphy lab (LMI, DIR, NIAID, NIH), who have shown that plerixafor (a potent inhibitor of CXCR4 activity also inhibitsthe abnormally high activity of C-terminal truncated CXCR4 in WHIM syndrome. This has led to a clinical trial conducted by Dr. McDermott on which we are principle collaborators examining the effect of plerixafor to treat patients with WHIM syndrome, finding that this agent increases the number of circulating neutrophils, B-lymphocytes and T-lymphocytes in these patients (McDermott D, et al. Blood 2014, 123:2308-16). Dr. McDermott has also identified a patient with WHIM syndrome who because of a chromosome loss event in a marrow stem cell, eliminated the dominant effect WHIM mutation from that cell, resulting in correction of the WHIM mutation with expansion of that corrected stem cells compartment.(McDermott D, et al. Cell 2015, 160:686-99). This has led to a new patent discovery that may be clinically applicable to enhancing bone marrow transplant engraftment (Gao J, et al. 2014, Patent pending: 62/026,138; US application). 3. New treatments for allogeneic transplant related graft versus host disease (GVHD): We have shown for the first time that a highly specific agonists (activators) of the Adenosine A2A receptor can prevent graft versus host disease in a single mismatch model of GVHD. Since these highly specific Adenosine A2A small molecule agonists are also in commercial Phase I and II clinical trials to treat the inflammation of asthma and chronic obstructive pulmonary disease there is also real potential of this class of agents in the future being applied to the GVHD prevention in the clinic. 4. Interactions of neutrophils with bacterial pathogens: We contributed to collaborative work from the Leto laboratory showing that release of cystic fibrosis airway inflammatory markers from Pseudomonas aeruginosa-stimulated human neutrophils Involves NADPH oxidase-dependent extracellular DNA trap formation (Yoo DG, et al. J Immunol 2014, 192:4728-38). In other studies with the Gallin laboratory (LHD, NIAID) we have collaborated in achieving better understanding of the potential role of the NADPH oxidase related oxidants in causing atherosclerosis (Sibley CT, et al. Circulation 2014, 130:2031-9). We reported about infection with a new type of fungus in patients with chronic granulomatous disease (De Ravin SS, et al. J Clin Microbiol 2014, 52:2726-9).
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