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    Barcoding of Macaque Hematopoietic Stem and Progenitor Cells: A Robust Platform to Assess Vector Genotoxicity

    Cover for Barcoding of Macaque Hematopoietic Stem and Progenitor Cells: A Robust Platform to Assess Vector Genotoxicity
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    View/Open: Yabe_georgetown_0076D_14170.pdf (7.0MB) Bookview

    Creator
    Yabe, Idalia
    Advisor
    Dunbar, Cynthia E
    Casey, John L
    ORCID
    0000-0003-1679-7053
    Abstract
    Gene therapies using integrating retroviral vectors to modify hematopoietic stem and progenitor cells have shown great promise for treatment of immune system and hematologic diseases. However, activation of proto-oncogenes via insertional mutagenesis has resulted in the development of leukemia. I have utilized cellular “barcoding” to investigate the impact of different vector designs on the clonal behavior of HSPC during in vivo expansion as a quantitative surrogate assay for genotoxicity in a non-human primate model with high relevance for human biology. I transplanted two rhesus macaques with autologous CD34+ HSPC transduced with three lentiviral vectors containing different promoters/enhancers of a predicted range of genotoxicities, each containing a high diversity barcode library that uniquely tags each individual transduced HSPC. Analysis of clonal output from thousands of individual HSPC transduced with these barcoded vectors revealed sustained clonal diversity, with no progressive dominance of clones containing any of the three vectors for up to almost three years post-transplantation. This data supports a low genotoxic risk for lentiviral vectors in HSPC, even those containing strong promoters/enhancers. Additionally, this flexible system can be used for testing of future vector designs.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1054986
    Date Published
    2019
    Subject
    gene therapy; genotoxicity; lentivirus; non-human primate; Cytology; Cellular biology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    127 leaves
    Collections
    • Graduate Theses and Dissertations - Microbiology & Immunology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility