Experimental Approaches to Hemophilia Gene Therapy: Gene Transfer Into Hematopoietlc Stem Cells

摘要

Autologous transplantation of gene-modified hematopoietic stem and progenitor cells (HPC) is currently evaluated for treatment of monogeneic hematopoietic disorders. Clinical studies have successfully used retroviral gene transfer into HPC to correct X-linked severe combined immunodeficiency (X-SCID) [1,2]. We currently evaluate gene transfer into HPC for hemophilia A gene therapy. Transplantation of HPC transduced with a gene for coagulation factor VIII (FVIII) may potentially provide a permanent pool of FVIII-expressing hematopoietic cells. In addition, immune tolerance against neo-antigenic FVIII might be achieved as reported for other transgenes in animal models. However, it has been unclear whether cells of hematopoietic origin are capable of FVIII biosynthesis and secretion, because transplantation of FVIII-transduced bone marrow cells into conditioned mice did not result in the expression of detectable FVIII in the plasma [3,4]. Others have found that certain myeloid cell lines were able to efficiently produce FVIII after transduction in vitro [5, 6]. We therefore studied the expression of recombinant FVIII after gene transfer into various hematopoietic cell types.