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.
Highlights
X-linked severe combined immunodeficiency (SCID-X1) is a life-threatening immunodeficiency disorder, characterized by defective T and natural killer (NK) cell production and the development of functionally impaired B cells that lack the capacity to produce immunoglobulins
Our findings demonstrated that the integration sites of the foamy virus (FV) vector were significantly less likely to be located within or near transcriptional start sites compared to those of a conventional RV vector, suggesting that the FV vector had a lower risk for insertion-mediated genotoxicity
We showed the successful reconstitution of functionally active T and B cells after the transplantation of hematopoietic stem cells (HSCs) containing a cc-FV vector into ccKO recipient mice
Summary
X-linked severe combined immunodeficiency (SCID-X1) is a life-threatening immunodeficiency disorder, characterized by defective T and natural killer (NK) cell production and the development of functionally impaired B cells that lack the capacity to produce immunoglobulins. These defects result in a profound reduction in the development of both cellular and humoral immunity. Bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical siblings can cure the disease with a success rate of approximately 90%. BMT from non-HLA-identical donors results in lower survival rates due to a high risk for complications such as graft-versus-host disease, graft rejection, and incomplete T cell engraftment [2,3]. Gene therapy approaches have been developed as an alternative treatment option for those patients lacking appropriate donors
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