CRISPR-based anti-viral therapeutics to eliminate EBV-associated post-transplant lymphoproliferative disease

Information

  • Research Project
  • 9047389
  • ApplicationId
    9047389
  • Core Project Number
    R43AI122529
  • Full Project Number
    1R43AI122529-01
  • Serial Number
    122529
  • FOA Number
    PA-14-071
  • Sub Project Id
  • Project Start Date
    1/1/2016 - 8 years ago
  • Project End Date
    6/30/2017 - 6 years ago
  • Program Officer Name
    MINNICOZZI, MICHAEL
  • Budget Start Date
    1/1/2016 - 8 years ago
  • Budget End Date
    6/30/2017 - 6 years ago
  • Fiscal Year
    2016
  • Support Year
    01
  • Suffix
  • Award Notice Date
    12/21/2015 - 8 years ago
Organizations

CRISPR-based anti-viral therapeutics to eliminate EBV-associated post-transplant lymphoproliferative disease

? DESCRIPTION (provided by applicant): Post-transplant lymphoproliferative disease (PTLD) is one of the most serious and potentially fatal post-transplant complications. Frequently, PTLD is triggered in the transplant recipient by the transfer of latent Epstein-Barr virus (EBV) present in the donor organ or tissue. The risk of PTLD is even higher when the donor is EBV seropositive and the recipient seronegative. Pervasiveness of EBV infection in the population is such that avoiding donor grafts infected with EBV is not a viable strategy. Current clinical practices of PTLD prevention requires patients to undergo 1) long term prophylactic antiviral regimens, 2) frequent monitoring via blood draws, and 3) adjustment of immunosuppression dosage, which can potentially lead to graft rejection. All these lead to high cost and high patient morbidity. There is also currently no antiviral drug that can treat the latent EBV infection because existing antiviral drugs only target proteins, and as such can only attack actively replicating virus. Overall, there is need to develop a more efficacious and specific way to prevent PTLD and its associated co-morbidities. The long term objective of this proposal is to eliminate the risk of donor-derived, EBV-associated PTLD for the ~50,000 annual tissue and organ transplant recipients in the US. It is hypothesized that a highly specific anti-viral therapeutic using CRISPR/Cas9 to directly target destruction of the EBV DNA genome would be able to eliminate the latent EBV reservoir in donor allografts. By treating the graft ex-vivo prior to transplantatio using this nuclease-based technology, the risk of donor EBV-derived PTLD is eliminated. Preliminary results demonstrate that this technology can successfully reduce viral load in patient-derived Burkitt's lymphoma cells with latent EBV infection, and can induce dramatic proliferation arrest reactivation of apoptotic pathways. These results demonstrate success of this technology in eliminating latent EBV virus from a cell line without observing any obvious cytotoxicity, thus this proposal aims to extend this work and evaluate the feasibility of this therapeutic approach in primary human blood samples in the context of hematopoietic cell transplants (HCT). This Phase I study will lay the foundation for future work to demonstrate efficacy and safety of this therapeutic in animal models and for solid organ transplant applications, and eventually for human trials. Specific Aim 1: Establish the efficacy of CRISPR/Cas9 anti-viral therapeutics in eliminating EBV infection from naturally infected EBV seropositive bone marrow samples, and evaluate associated effects on HSC function. Specific Aim 2: Investigate the safety of CRISPR/Cas9 anti-viral therapeutics in the context of eliminating EBV from EBV+ primary bone marrow samples, and optimize treatment conditions to minimize off-target effects on human host genome.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R43
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    149972
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:149972\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    AGENOVIR CORPORATION
  • Organization Department
  • Organization DUNS
    079720113
  • Organization City
    SOUTH SAN FRANCISCO
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    940801913
  • Organization District
    UNITED STATES