Megakaryocyte- and megakaryocyte precursor–related gene therapies

David A. Wilcox

Article Figures & Data


  • Figure 1

    Promising strategies for megakaryocyte gene transfer. Displayed is a schematic diagram that summarizes 3 strategies currently being examined for megakaryocyte modification including: transplantation of cytokine-mobilized CD34+ PBSCs transduced with a lentiviral vector; direct injection of lentiviral vector into the bone marrow space to transduce HSCs; and lentiviral vector transduction of iPSCs dedifferentiated from peripheral blood mononuclear cells followed by transfusion of genetically altered platelets into the patient. Although each method focuses on modification of the HSCs with a lentiviral vector under the transcriptional control of a megakaryocyte-specific gene promoter, there is significant contrast in procuring the HSC target cell as well as different strategies for accomplishing megakaryocyte manipulation. HSC differentiation along the megakaryocyte lineage is depicted by stage from HSCs within the bone marrow to formation of proplatelets, preplatelets, and finally mature platelets within the vascular space. The cartoon person illustrates the routes of collection and transfusion of genetically modified cells and a potential point of injection for LV within the bone marrow space. PBSCs are all HSCs. BM, bone marrow; LV, lentivector.


  • Table 1

    Advantages and disadvantages of new strategies to correct hemophilia A

    Gene vectorTargetGene promoterFVIIIReferenceAdvantagesDisadvantages
    AAVEndothelium liverLiver specificBDD FVIII modified61+No pre-tx conditioning−Vector size limitation
    +Shown safe in humans−Use only in patients without AAV inhibitor and without FVIII inhibitor
    +No reports of mutagenesis−Cell death ends treatment
    LVHSC CD34+ PBSCsNonspecific CMVBDD FVIII modified63+Use with AAV inhibitors−Submyeloablative conditioning required
    −Mutagenesis risk
    +Theoretically 1 treatment−Use only without FVIII inhibitor
    LVHSC CD34+ PBSCsMeg-GPIBABDD FVIII modified67+Use with AAV and FVIII inhibitors−Submyeloablative conditioning required
    +Theoretically 1 treatment−Mutagenesis risk
    GPIBA gene promoter associated with low plt production
    LVHSC BMMeg-GPIBABDD FVIII72+No pre-tx conditioning−Target cell not purified for transduction
    −Mutagenesis risk
    +Use with AAV and FVIII inhibitorsGPIBA gene promoter associated with low plt production
    +Theoretically 1 treatment−Feasibility in humans?
    LVHSC CD34+ PBSCsMeg-ITGA2BBDD FVIII31+Use with AAV and FVIII inhibitors−Submyeloablative conditioning required
    +Normal plt production−Mutagenesis risk
    • BM, bone marrow; CMV, promoter of the cytomegalovirus; LV, lentiviral vector; Meg, megakaryocyte-specific; plt, platelet; tx, transplant.