Evaluation of Maternal Safety Following Prenatal Cell and Gene Therapy for Hemophilia A

ABSTRACT Objective Maternal safety is extremely important in prenatal therapies, especially if the product could impact the pregnant women. Methods This study uses fetal sheep as a model to investigate whether intraperitoneal administration of human placental cells modified to encode a bioengineered fVIII transgene (mcoET3) exposes the ewes to the transplanted product (PLC‐mcoET3) or its secreted proteins, thereby inducing an immune response. Results Mixed‐lymphocyte reactions and sensitive multiplex bead assays demonstrated that prenatal treatment did not immunize the ewes to the transplanted cells or induce anti‐HLA Class I and Class II antibodies. ELISpot assays and mcoET3‐specific ELISAs demonstrated the absence of mcoET3‐specific T h 1 / T h 2 cells and anti‐mcoET3 IgGs, respectively. To assess transfer of PLC‐mcoET3 to ewes, nucleated cells in peripheral blood, and placental and umbilical cord tissues collected at birth were analyzed for the presence of human cells or the mcoET3 transgene. All tissues were found to be histologically normal and negative for human cells/mcoET3 transgene. Conclusion Overall, these studies suggest that the administration of PLC‐mcoET3 to the fetus during gestation does not result in detectable maternal exposure to the cells or gene products, attesting to the safety of this approach.