Retroviral-Mediated Gene Correction for X-Linked Severe Combined Immunodeficiency

• Published in: Blood Vol. 87; no. 8; pp. 3097 - 3102
• Main Authors: Candotti, Fabio, Johnston, James A., Puck, Jennifer M., Sugamura, Kazuo, O'Shea, John J., Blaese, R.Michael
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.1996; The Americain Society of Hematology
• Subjects: AIDS/HIV; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biological and medical sciences; Cell Line, Transformed; Feasibility Studies; Genetic Complementation Test; Genetic Therapy; Genetic Vectors - genetics; Herpesvirus 4, Human; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Interleukin-2 - pharmacology; Interleukin-4 - pharmacology; Janus Kinase 1; Janus Kinase 3; Lymphocyte Activation - drug effects; Male; Medical sciences; Phosphorylation; Protein Processing, Post-Translational; Protein-Tyrosine Kinases - metabolism; Receptors, Interleukin-2 - biosynthesis; Receptors, Interleukin-2 - genetics; Recombinant Fusion Proteins - metabolism; Retroviridae - genetics; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - pathology; Severe Combined Immunodeficiency - therapy; Transfection; X Chromosome - genetics; Human; Immunopathology; Sex linked character; Gamma-Peptide chain; Cytokine; In vitro; Genetic disease; Signal transduction; Interleukin 4; Membrane receptor; Treatment; Complementary DNA; Interleukin 2; Transduction; X-Chromosome; Combined immune deficiency; Gene therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.8.3097.bloodjournal8783097

X-linked severe combined immunodeficiency (XSCID) is a lethal disease caused by a defect in the gene encoding the common γ chain (γc) 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 lympho-hematopoietic 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 γc was used to transduce Epstein-Barr virus-transformed B-cell lines derived from patients with XSCID. After transduction, XSCID cells newly expressed γc on the ceil surface at levels comparable to those observed on B-cell lines obtained from normal donors. Moreover, the reconstituted γc 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. This is a US government work. There are no restrictions on its use.