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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2671-2679. Prepublished online as a Blood First Edition Paper on June 21, 2005; DOI 10.1182/blood-2004-12-4619. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-12-4619v1 106/8/2671    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 Fang, J. Articles by Wilcox, D. A. Search for Related Content PubMed PubMed Citation Articles by Fang, J. Articles by Wilcox, D. A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Free Research Articles Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Therapeutic expression of the platelet-specific integrin, IIb3, in a murine model for Glanzmann thrombasthenia Juan Fang, Kairbaan Hodivala-Dilke, Bryon D. Johnson, Lily M. Du, Richard O. Hynes, Gilbert C. White, II, and David A. Wilcox From the Department of Pediatrics, Medical College of Wisconsin, Milwaukee; the Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee; the Cell Adhesion and Disease Lab, Department of Tumour Biology, Cancer Research UK Clinical Center, Bart's and The London Queen Mary's School of Medicine and Dentistry, John Vane Science Center, Charterhouse Square, London, United Kingdom; the Howard Hughes Medical Institute, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge; the Center for Thrombosis and Hemostasis, Departments of Medicine and Pharmacology, University of North Carolina, Chapel Hill; and the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee. Integrins mediate the adhesion of cells to each other and to the extracellular matrix during development, immunity, metastasis, thrombosis, and wound healing. Molecular defects in either the - or -subunit can disrupt integrin synthesis, assembly, and/or binding to adhesive ligands. This is exemplified by the bleeding disorder, Glanzmann thrombasthenia (GT), where abnormalities of the platelet-specific integrin, IIb3, prevent platelet aggregation following vascular injury. We previously used a retrovirus vector containing a cDNA cassette encoding human integrin 3 to restore integrin IIb3 on the surface of megakaryocytes derived from peripheral blood stem cells of GT patients. In the present study, bone marrow from 3-deficient (3–/–) mice was transduced with the ITG3-cassette to investigate whether the platelet progeny could establish hemostasis in vivo. A lentivirus transfer vector equipped with the human ITGA2B gene promoter confined transgene expression to the platelet lineage. Human 3 formed a stable complex with murine IIb, effectively restoring platelet function. Mice expressing significant levels of IIb3 on circulating platelets exhibited improved bleeding times. Intravenous immunoglobulin effectively diminished platelet clearance in animals that developed an antibody response to IIb3. These results indicate the feasibility of targeting platelets with genetic therapies for better management of patients with inherited bleeding disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Viral rescue of murine Glanzmann thrombasthenia Jerry Ware Blood 2005 106: 2596. [Full Text] [PDF] This article has been cited by other articles: B. S. Coller and S. J. Shattil The GPIIb/IIIa (integrin {alpha}IIb{beta}3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend Blood, October 15, 2008; 112(8): 3011 - 3025. [Abstract] [Full Text] [PDF] T. Ohmori, Y. Kashiwakura, A. Ishiwata, S. Madoiwa, J. Mimuro, and Y. Sakata Silencing of a Targeted Protein in In Vivo Platelets Using a Lentiviral Vector Delivering Short Hairpin RNA Sequence Arterioscler Thromb Vasc Biol, October 1, 2007; 27(10): 2266 - 2272. [Abstract] [Full Text] [PDF] E. F. Plow and Y.-Q. Ma Inside-out, outside-in: what's the difference? Blood, April 15, 2007; 109(8): 3128 - 3129. [Full Text] [PDF] Z. Zou, H. Chen, A. A. Schmaier, R. O. Hynes, and M. L. Kahn Structure-function analysis reveals discrete {beta}3 integrin inside-out and outside-in signaling pathways in platelets Blood, April 15, 2007; 109(8): 3284 - 3290. [Abstract] [Full Text] [PDF] T. Ohmori, J. Mimuro, K. Takano, S. Madoiwa, Y. Kashiwakura, A. Ishiwata, M. Niimura, K. Mitomo, T. Tabata, M. Hasegawa, et al. Efficient expression of a transgene in platelets using simian immunodeficiency virus-based vector harboring glycoprotein Ib{alpha} promoter: in vivo model for platelet-targeting gene therapy FASEB J, July 1, 2006; 20(9): 1522 - 1524. 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