title: Comparison of three retroviral vector systems for transduction of nonobese diabetic/severe combined immunodeficiency mice repopulating human CD34+ cord blood cells.
abstract: The use of recombinant vectors based on wild-type viruses that are absent in humans and are not associated with any disease in their natural animal hosts or in accidentally infected humans would add an additional level of safety for human somatic gene therapy approaches. These criteria are fulfilled by foamy viruses (FVs), a family of complex retroviruses whose members are widely found among mammals and are apathogenic in all hosts. Here, we show by comparison of identically designed vector constructs that recombinant retroviral vectors based on FVs were as efficient as lentiviral vectors in transducing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice repopulating human CD34(+) cord blood (CB) cells. The FV vector was able to achieve gene transfer levels up to 84% of engrafted human cells in a short overnight transduction protocol. In contrast, without prestimulation of the target cells, a human immunodeficiency virus type 1 (HIV-1)-based lentiviral vector pseudotyped with gibbon ape leukemia virus envelope (GALV Env) was nearly as inefficient as murine leukemia virus (MLV)-based oncoretroviral vectors in transducing NOD/SCID repopulating cells. The same HIV vector pseudotyped with the vesicular stomatitis virus glycoprotein G (VSV-G) achieved high marking efficiency. Clonality analysis of bone marrow samples showed oligoclonal hematopoiesis with single to multiple insertions per cell, both for FV and HIV vectors. These data demonstrate that vectors based on FVs warrant further investigation and development for medical use.
authors.affiliation: Klinik für Pädiatrische Hämatologie und Onkologie, Zentrum für Kinderheilkunde, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Leurs
authors.forename: Michael
authors.initials: M
authors.lastname: Jansen
authors.forename: Karen E
authors.initials: KE
authors.lastname: Pollok
authors.forename: Martin
authors.initials: M
authors.lastname: Heinkelein
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Manuela
authors.initials: M
authors.lastname: Wissler
authors.forename: Dirk
authors.initials: D
authors.lastname: Lindemann
authors.forename: Christof
authors.initials: C
authors.lastname: Von Kalle
authors.forename: Axel
authors.initials: A
authors.lastname: Rethwilm
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D002460:Cell Line; D005312:Fetal Blood / Q000166:cytology; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D015497:HIV-1 / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D009052:Leukemia Virus, Murine / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012190:Retroviridae / Q000235:genetics*; D016092:Spumavirus / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins