Accomplishments toward the goals of this project in the past fiscal year include: 1. We have developed an efficient method to 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. 2. In work with our collaborators in the FDA using a proteome analysis method, we have identified protein markers that define the quality of iPSC (Pripuzova NS, et al. Stem Cell Res 2015, 14:323-38). 3. In a study that is listed as the key scientific advance in this Annual report, we have defined the key molecular markers and regulators of the differentiation of hematopoietic stem cells and mature myeloid cells from human iPS cells. This could lead to novel cellular therapies to correct disorders of the blood forming system including correction of primary immune deficiencies. (Sweeney CL, et al, Stem Cells. 2016 34:1513). 4. We have shown for the first time that a pregnancy related protein PG9 can induce development of regulatory T cells, through the TGF-beta1 pathway (Jones K, et al. PLoS One 2016, 11:e0158050). In related studies in progress, PG9 and in particular the related protein PG1 can prevent graft versus host disease in a single mismatch mouse model of GVHD. This may lead to new treatments for GVHD following hematopoietic stem cells transplant. 5. We have shown for the first time that the use of post-transplant Cytoxan can facilitate related donor parental haploidentical transplant to cure infection and cure chronic granulomatous disease in a patient with a severe fungal infection of the chest and heart without development of significant graft versus host disease (Parta M, et al, J Clin Immunol 35:675-80). 6. We have published the results of a clinical trial of lentivector transduced autologous hematopoietic stem cells for X-linked severe combined immune deficiency in which older children and young adults achieved correction of both cellular and humoral immunity (De Ravin SS, et al. Sci Transl Med 8:335ra57). 7. We have published the results of studies designed to achieve efficient gene editing in human CD34+ hematopoietic stem cells using zinc finger nuclease mRNA targeting the AAVS1 safe harbor site by electroporation delivery followed by delivery of a gene insertion template packaged in AAV6. This was used to deliver either a fluorescent marker (Venus) to the site with >50% efficiency or to deliver the gp91phox cDNA to correct X-linked chronic granulomatous disease to the site with >15% efficiency (De Ravin SS, et al. Nat Biotechnol 34:424-9). 8. 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 inhibits the 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). This trial and a related double blinded trial of plerixafor for WHIM syndrome are in progress. 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). Patients with other novel mutations in CXCR4 have been described (Liu Q, J Clin Immunol 36:397-405). 9. As collaborators with the Holland lab we have contributed to the discovery of a new immunodeficiency caused by mutations in the gene encoding WDR1, and actin regulating protein (Kuhns DB, et al. Blood 2016, August e-pub ahead of print ). Our lab developed iPSC from patients with WDR1 deficiency and recapitulated the defect in neutrophils and monocytes differentiated from the iPSC in this model as one part of our contribution to these studies.
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