BACKGROUND: X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor gamma chain (gamma(c)), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is successful if HLA-matched family donors are available, but HLA-mismatched procedures are associated with substantial morbidity and mortality. We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector. METHODS: Four children with SCID-X1 were enrolled. Autologous CD34-positive haemopoietic bone-marrow stem cells were transduced ex vivo and returned to the patients without preceding cytoreductive chemotherapy. The patients were monitored for integration and expression of the gamma(c) vector and for functional immunological recovery. FINDINGS: All patients have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two. No serious adverse events have been recorded. T cells responded normally to mitogenic and antigenic stimuli, and the T-cell-receptor (TCR) repertoire was highly diverse. Where assessable, humoral immunity, in terms of antibody production, was also restored and associated with increasing rates of somatic mutation in immunoglobulin genes. INTERPRETATION: Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity.
BACKGROUND: X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor gamma chain (gamma(c)), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is successful if HLA-matched family donors are available, but HLA-mismatched procedures are associated with substantial morbidity and mortality. We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector. METHODS: Four children with SCID-X1 were enrolled. Autologous CD34-positive haemopoietic bone-marrow stem cells were transduced ex vivo and returned to the patients without preceding cytoreductive chemotherapy. The patients were monitored for integration and expression of the gamma(c) vector and for functional immunological recovery. FINDINGS: All patients have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two. No serious adverse events have been recorded. T cells responded normally to mitogenic and antigenic stimuli, and the T-cell-receptor (TCR) repertoire was highly diverse. Where assessable, humoral immunity, in terms of antibody production, was also restored and associated with increasing rates of somatic mutation in immunoglobulin genes. INTERPRETATION: Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity.
Authors: Sheng Zhou; Disha Mody; Suk See DeRavin; Julia Hauer; Taihe Lu; Zhijun Ma; Salima Hacein-Bey Abina; John T Gray; Michael R Greene; Marina Cavazzana-Calvo; Harry L Malech; Brian P Sorrentino Journal: Blood Date: 2010-05-10 Impact factor: 22.113
Authors: Alice F Tarantal; Francesca Giannoni; C Chang I Lee; Jennifer Wherley; Teiko Sumiyoshi; Michele Martinez; Christoph A Kahl; David Elashoff; Stan G Louie; Donald B Kohn Journal: Mol Ther Date: 2012-01-31 Impact factor: 11.454
Authors: Anna Paruzynski; Anne Arens; Richard Gabriel; Cynthia C Bartholomae; Simone Scholz; Wei Wang; Stephan Wolf; Hanno Glimm; Manfred Schmidt; Christof von Kalle Journal: Nat Protoc Date: 2010-07-08 Impact factor: 13.491
Authors: Byoung Y Ryu; Marguerite V Evans-Galea; John T Gray; David M Bodine; Derek A Persons; Arthur W Nienhuis Journal: Blood Date: 2007-11-08 Impact factor: 22.113