Reprogrammed T Cells to prevent graft versus host disease

PROJECT SUMMARY ABSTRACT The objective of this proposal is to develop an efficient and robust method to epigenetically reprogram na ve human T cells into regulatory T cellsTregsthat can prevent graft versus host diseaseGvHDOur short term goal for Phase I of the STTR award is to demonstrate that we can epigenetically reprogram na ve T cells using CRISPR Casbased technology into immunosuppressive cells that have the protein markergene expressionand epigenetic regulatory profiles of TregsThis will motivate Phase II of the STTRwhere we will test the epigenetically reprogrammed Tregs in a humanized mouse model of graft versus host diseaseThe data obtained during the STTR will position the therapy for clinical trials to prevent GvHD in hematopoietic cell transplantationThere is a clinical need to improve patient outcomes in allogeneic hematopoietic cell transplantationHCTdue to the high incidencemorbiditityand mortality associated with GvHDApproximately half of all HCTs utilize hematopoietic cells from unrelated donorsand approximatelypatients will undergo this procedure per year worldwideDespite improved diagnostics to match the most immunogenic antigens on the donor cells with those of the recipientup toof allogeneic HCT recipients will develop GvHD as a result of their graftOnlyof HCT recipients that develop GvHD surviveyears beyond the transplant procedureGvHD is mediated by donor T cells that recognize polymorphisms in the protein coding genome of the graft and the recipientand these reactive T cells can be suppressed by TregsWe will utilize CRISPR Casbased epigenetic editing tools to reprogram na ve human T cellswhich be easily collected from whole blood by apheresis or density gradient centrifugationinto immunosuppressive TregsWe will first perform a high throughput screens of candidate Tregspecific gene regulatory elements that we have identified through computational analysis of epigenomic dataWe will then validate that these elements can be activated by CRISPR Casbased epigenome modification tools that we have developed to generate T cells with the phenotypein vitro suppressive propertiesgene expressionand chromatin regulatory profile of Tregs!PROJECT NARRATIVE This STTR proposal seeks to identify gene regulatory elements thatwhen activatedallow T cells to adopt an immunosuppressiveregulatory function that is critical to prevent graft versus host diseaseGvHDafter hematopoietic cell transplantationHCTfrom another individualThere is a significant clinical need for improved immunosuppressive therapies that can prevent GvHD because up toof HCT patients develop GvHD and onlyof those with the disease survive more thanyearsIn this STTRwe will reprogram graft T cells that are potentially reactive towards host antigens into regulatory T cells using tools that activate the expression of specific genes controlling the immunosuppressive function of these cells!