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Reprogrammed T Cells to prevent graft versus host disease

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI136755-01A1
Agency Tracking Number: R41AI136755
Amount: $221,507.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA16-303
Solicitation Year: 2016
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-02-08
Award End Date (Contract End Date): 2019-01-31
Small Business Information
Durham, NC 27712-3006
United States
DUNS: 079953960
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 660-8275
Business Contact
Phone: (609) 513-9239
Research Institution
BAHAMA, NC 27503-9692
United States

 Domestic Nonprofit Research Organization

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!

* Information listed above is at the time of submission. *

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