Thornhill, SI; Schambach, A; Howe, SJ; Ulaganathan, M; Grassman, E; Williams, D; ... Thrasher, AJ; + view all Thornhill, SI; Schambach, A; Howe, SJ; Ulaganathan, M; Grassman, E; Williams, D; Schiedlmeier, B; Sebire, NJ; Gaspar, HB; Kinnon, C; Baum, C; Thrasher, AJ; - view fewer (2008) Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency. MOL THER , 16 (3) 590 - 598. 10.1038/sj.mt.6300393.
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Gene therapy for X-linked severe combined immunodeficiency (SCID-X1) has proven highly effective for long- term restoration of immunity in human subjects. However, the development of lymphoproliferative complications due to dysregulated proto-oncogene expression has underlined the necessity for developing safer vector systems. To reduce the potential for insertional mutagenesis, we have evaluated the efficacy of self-inactivating (SIN) gammaretroviral vectors in cellular and in vivo models of SCID-X1. Vectors incorporating an internal human elongation factor-1a regulatory element were capable of fully restoring the lymphoid differentiation potential of gamma c-deficient lineage negative cells. Multilineage lymphoid reconstitution of a murine model was achieved at a similar level to that achieved by a conventional longterminal repeat (LTR)-regulated vector used in previous clinical trials. Functional proliferative responses to mitogenic stimuli were also restored, and serum immunoglobulin levels were normalized. The reduced mutagenic potential conferred by SIN vector configurations and alternative non-LTR-based regulatory elements, together with proven efficacy in correction of cellular defects provides an important platform for development of the next phase of clinical trials for SCID-X1.
|Title:||Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency|
|Keywords:||HEMATOPOIETIC STEM-CELLS, RECEPTOR-GAMMA CHAIN, RETROVIRAL VECTORS, IMMUNE RECONSTITUTION, TRANSGENE EXPRESSION, LYMPHOID DEVELOPMENT, LENTIVIRAL VECTORS, T-CELLS, MICE, TRANSPLANTATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Infection and Immunity > ICH - Molecular Immunology Unit|
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