Prostaglandin E(2) Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells

Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34(+) hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E(2) (PGE(2)) as a positive mediator of lentiviral transduction of CD34(+) cells. Supplementation with PGE(2) increased lentiviral vector (LVV) transduction of CD34(+) cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34(+) cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE(2) increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE(2) improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE(2) may be useful in clinical gene therapy applications using lentivirally modified HSPCs.