Gene Therapy: Graft-versus-host Disease (GVHD) in NSG™ (NOD.Cg-Prkdc Il2rg/SzJ) Mice Transplanted with CD34 Human Hematopoietic Stem Cells.

A therapeutic option for monogenic disorders is gene therapy with -transduced autologous hematopoietic stem cells (HSCs). Safety or efficacy studies of -modified HSCs are conducted in humanized mouse models after ablation of the murine bone marrow and transfer of human CD34 HSCs. Engrafted human CD34 cells migrate to bone marrow and differentiate into various human hematopoietic lineages. A 12-week study was conducted in NSG™ mice to evaluate engraftment, differentiation, and safety of human CD34 cells that were transduced () with a proprietary lentiviral vector encoding a human gene (BMRN-1) or a mock (green fluorescent protein) vector. Several mice intravenously injected with naive CD34 cells or transduced CD34 cells had variable lymphohistiocytic inflammatory cell infiltrates and microgranulomas in the liver and lungs consistent with graft-versus-host disease (GVHD). Spleen, bone marrow, stomach, reproductive tract, but not the skin had similar inflammatory changes. viral transduction of CD34 cells did not impact engraftment or predispose to xenogeneic GVHD.