title: Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector.
abstract: X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor γ chain (γc) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the γc gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human γc. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from γc-knockout (γc-KO) mice were infected with the FV vector and transplanted into γc-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID-X1.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan ; Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Horino
authors.forename: Toru
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Takanori
authors.initials: T
authors.lastname: So
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagashima
authors.forename: Shu-Lan
authors.initials: SL
authors.lastname: Sun
authors.forename: Miki
authors.initials: M
authors.lastname: Sato
authors.forename: Atsuko
authors.initials: A
authors.lastname: Asao
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Haji
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sasahara
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016092:Spumavirus / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*
chemical_list: D053631:Interleukin Receptor Common gamma Subunit