title: Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer.
abstract: Janus kinase-3 (JAK3) deficiency has recently been identified as a cause of severe combined immunodeficiency (SCID) in humans. We used a mouse model of Jak3-deficient SCID to test a gene therapy approach for treatment of this disease. Transfer of a Jak3 retroviral vector to repopulating hematopoietic stem cells resulted in increased numbers of T and B lymphocytes, reversal of hypogammaglobulinemia, restoration of T-cell activation upon stimulation with mitogens, and development of an antigen-specific immune response after immunization. Analysis for vector copy number in lymphoid and myeloid populations showed a large in vivo selective advantage for Jak3-expressing lymphoid cells. These results show that gene replacement is a feasible treatment strategy for this disease and that naturally occurring in vivo selection of corrected cells is an important advantage of this approach.
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Bunting
authors.forename: M Y
authors.initials: MY
authors.lastname: Sangster
authors.forename: J N
authors.initials: JN
authors.lastname: Ihle
authors.forename: B P
authors.initials: BP
authors.lastname: Sorrentino
mesh_terms: D000361:Agammaglobulinemia / Q000209:etiology / Q000628:therapy; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D053616:Janus Kinase 3; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D012190:Retroviridae; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3