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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-05-1423. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-05-1423v1 101/6/2159    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Klein, C. Articles by Snapper, S. B. Search for Related Content PubMed PubMed Citation Articles by Klein, C. Articles by Snapper, S. B. Related Collections Immunobiology Transplantation Signal Transduction Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 March 2003, Vol. 101, No. 6, pp. 2159-2166 GENE THERAPY Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice Christoph Klein, Deanna Nguyen, Ching-Hui Liu, Atsushi Mizoguchi, Atul K. Bhan, Hiroaki Miki, Tadaomi Takenawa, Fred S. Rosen, Fred W. Alt, Richard C. Mulligan, and Scott B. Snapper From the Division of Molecular Medicine and Pediatric Hematology/Oncology, Howard Hughes Medical Institute, The Children's Hospital, Boston, MA; the Center for Blood Research, Boston, MA; the Gastrointestinal Unit (Medical Services), Immunopathology Unit, and the Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston, MA; the Departments of Pediatrics, Genetics, Medicine, and Pathology, Harvard Medical School, Boston, MA; and the Department of Biochemistry, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo; Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany. The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency that is caused by mutations in the recently identified WASP gene. WASP plays an important role in T-cell receptor-mediated signaling to the actin cytoskeleton. In these studies we assessed the feasibility of using retroviral gene transfer into WASP-deficient hematopoietic stem cells (HSCs) to rescue the T-cell signaling defect that is characteristic of WAS. Upon transplantation of WASP-deficient (WKO) HSCs that have been transduced with WASP-expressing retroviruses, mature B and T cells developed in normal numbers. Most importantly, the defect in antigen receptor-induced proliferation was significantly improved in T cells. Moreover, the susceptibility of colitis by WKO HSCs was prevented or ameliorated in recipient bone marrow chimeras by retrovirus-mediated expression of WASP. A partial reversal of the T-cell signaling defect could also be achieved following transplantation of WASP-deficient HSCs expressing the WASP-homologous protein N-WASP. Furthermore, we have documented a selective advantage of WT over WKO cells in lymphoid tissue using competitive repopulation experiments and Southern blot analysis. Our results provide proof of principle that the WAS-associated T-cell signaling defects can be improved upon transplantation of retrovirally transduced HSCs without overt toxicity and may encourage clinical gene therapy trials. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Bosticardo, F. Marangoni, A. Aiuti, A. Villa, and M. Grazia Roncarolo Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome Blood, June 18, 2009; 113(25): 6288 - 6295. [Abstract] [Full Text] [PDF] L. D. Notarangelo and R. Badolato Leukocyte trafficking in primary immunodeficiencies J. Leukoc. Biol., March 1, 2009; 85(3): 335 - 343. [Abstract] [Full Text] [PDF] L. S. Westerberg, M. A. de la Fuente, F. Wermeling, H. D. Ochs, M. C. I. Karlsson, S. B. Snapper, and L. D. 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