• Skinner, Amy (PI)

    Project: Research project

    Project Details


    Project summary: Knowledge of the molecular basis of blood and immune disorders along with the
    availabiltiy of technologies for the genetic manipulation and phenotypic correction of hematopoietic stem
    cells provides novel therapeutic opportunities. For example, near universal bone marrow failure in patients
    with Fanconi Anemia (FA) results in considerable morbidity and mortality. This coupled with the limited
    availability of suitable HLA-matched donors for curative allogeneic stem cell transplantation provides strong
    rationale to target autologous hematopoietic stem cells for stable genetic correction. Conventional
    approaches to stem cell modification most often utilize in vitro culture of target cell and viral or non-viral
    vector systems. This approach is not ideal for HSC from FA patients where a pro-apoptotic tendency and
    repopulation deficiency conspire to limit therapeutic chimerism from genetically corrected cells. Alternatively,
    dissemination and biosafety concerns present substantial impediments to intravenous injection of vector. I
    propose to develop a novel strategy for the systemic in situ delivery of HIV-derived retrovirus particles, to
    reconcile barriers to vector delivery and stem cell survival with the therapeutic potential of retroviral HSC
    modification. The overall hypothesis underlying my proposal is that the prolonged persistence of vector
    particles in hematopoietic cells combined with the inherent homing mechanisms of these cells can provide
    for targeted cellular delivery of vector particles to the bone marrow microenvironment. This innovative
    strategy is supported by the following observations. 1) Recent studies from our laboratory have revealed the
    unexpected uptake and delayed release of HIV vector particles from hematopoietic target cells and their
    retained ability for secondary transduction. 2) Hematopoietic cells possess cell surface molecules that direct
    their distribution after intravenous injection to the bone marrow. 3) Related approaches in cancer gene
    therapy provide precedent for the cellular delivery of particles to xenogenic tumor grafts in mice. The aim of
    my project is to elucidate the mechanistic basis for particle delivery, to provide proof of principle that in situ
    correction can restore HSC alkylator resistance in Fancc-/- mice, and to limit vector dissemination to non-
    targeted tissues.
    Relevance: The proposed research is a pre-clinical study that is of direct relevance to curative therapeutic
    approaches to single gene disorders affecting hematopoietic stem cells.
    Effective start/end date3/1/095/31/11


    • National Institutes of Health: $52,154.00
    • National Institutes of Health: $50,054.00


    • Medicine(all)


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