title: Retroviral-mediated gene correction for X-linked severe combined immunodeficiency.
abstract: X-linked severe combined immunodeficiency (XSCID) is a lethal disease caused by a defect in the gene encoding the common gamma chain (gamma-c) of the receptor for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. Allogeneic bone marrow transplantation, the current therapy of choice for this defect, is often complicated by graft-versus-host disease and/or incomplete reconstitution of B-lymphocyte functions. Correction of the gene defect at the level of the autologous lymphohematopoietic progenitors could therefore represent an improvement in the medical management of these patients. To study the feasibility of a gene therapy approach for XSCID, a retroviral vector expressing gamma-c was used to transduce Epstein-Barr virus-transformed B-cell lines derived from patients with XSCID. After transduction, XSCID cells newly expressed gamma-c on the cell surface at levels comparable to those observed on B-cell lines obtained from normal donors. Moreover, the reconstituted gamma-c restored function to the IL-2 and IL-4 receptors as shown by signal transduction mediated by phosphorylation of the JAK1 and JAK3 members of the Janus family of tyrosine kinases and by restoration of cellular proliferation in response to IL-2.
authors.affiliation: Clinical Gene Therapy Branch, NCHGR, National Institutes of Health, Bethesda, Maryland 20892-1852 USA.
authors.forename: F
authors.initials: F
authors.lastname: Candotti
authors.forename: J A
authors.initials: JA
authors.lastname: Johnston
authors.forename: J M
authors.initials: JM
authors.lastname: Puck
authors.forename: K
authors.initials: K
authors.lastname: Sugamura
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: R M
authors.initials: RM
authors.lastname: Blaese
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D005240:Feasibility Studies; D005816:Genetic Complementation Test; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D004854:Herpesvirus 4, Human; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D014960:X Chromosome / Q000235:genetics
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3