title: Self-inactivating gammaretroviral vectors for gene therapy of X-linked severe combined immunodeficiency.
abstract: 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-1alpha regulatory element were capable of fully restoring the lymphoid differentiation potential of gammac-deficient lineage negative cells. Multilineage lymphoid reconstitution of a murine model was achieved at a similar level to that achieved by a conventional long-terminal 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.
authors.affiliation: Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, London, UK.
authors.forename: Susannah I
authors.initials: SI
authors.lastname: Thornhill
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.forename: Meera
authors.initials: M
authors.lastname: Ulaganathan
authors.forename: Elke
authors.initials: E
authors.lastname: Grassman
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schiedlmeier
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015152:Blotting, Northern; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D017988:Gammaretrovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053632:X-Linked Combined Immunodeficiency Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*