Transduction of human NOD/SCID-repopulating cells with both lymphoid and myeloid potential by foamy virus vectors.
The efficiency of gene transfer into human hematopoietic stem cells by oncoretroviral vectors is too low for effective gene therapy of most hematologic diseases. Retroviral vectors based on the nonpathogenic foamy viruses (FV) are an alternative gene-transfer system. In this study, human umbilical cord blood CD34(+) cells were transduced with FV vectors by a single 10-h exposure to vector stocks and then injected into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice. At 5-7 weeks after transplantation, high transgene expression rates were observed in engrafted human hematopoietic cells, including over 60% of clonogenic progenitors. Significant transgene silencing did not occur. We developed an approach for expanding human cell populations derived from transplanted mice to show that multiple SCID repopulating cells (SRCs) had been transduced, including some that were capable of both lymphoid and myeloid differentiation. These findings demonstrate for the first time that human pluripotent (lympho-myeloid) hematopoietic stem cells repopulate NOD/SCID mice and can be efficiently transduced by FV vectors.
Josephson
Neil C
NC
Department of Medicine, Division of Hematology, University of Washington, Seattle, WA 98195, USA.
Vassilopoulos
George
G
Trobridge
Grant D
GD
Priestley
Greg V
GV
Wood
Brent L
BL
Papayannopoulou
Thalia
T
Russell
David W
DW
D000818:Animals; D015703:Antigens, CD / Q000097:blood; D018941:Antigens, CD19 / Q000097:blood; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001803:Blood Transfusion; D001854:Bone Marrow Cells / Q000166:cytology; D015704:CD4 Antigens / Q000097:blood; D003114:Colony-Forming Units Assay; D004921:Erythropoietin / Q000494:pharmacology; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000821:virology; D006801:Humans; D016130:Immunophenotyping; D007231:Infant, Newborn; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016092:Spumavirus / Q000235:genetics*; D019089:Stem Cell Factor / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014470:Umbilical Cord
D015703:Antigens, CD; D018941:Antigens, CD19; D015704:CD4 Antigens; D008164:Luminescent Proteins; D008565:Membrane Proteins; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D004921:Erythropoietin; D049452:Green Fluorescent Proteins