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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3700-3709. Prepublished online as a Blood First Edition Paper on December 30, 2003; DOI 10.1182/blood-2003-09-3217. This Article Full Text (PDF) All Versions of this Article: 2003-09-3217v1 103/10/3700    most recent Alert me when this article is cited Alert me if a correction is posted 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 Follenzi, A. Articles by Naldini, L. Search for Related Content PubMed PubMed Citation Articles by Follenzi, A. Articles by Naldini, L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted September 22, 2003 Accepted November 26, 2003 Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice Antonia Follenzi, Manuela Battaglia, Angelo Lombardo, Andrea Annoni, Maria G Roncarolo, and Luigi Naldini* Laboratory of Gene Transfer and Therapy, Institute for Cancer Research and Treatment (IRCC), University of Torino, Turin, Italy HSR-Telethon Institute for Gene Therapy, H. San Raffaele Scientific Institute, Milan, Italy HSR-Telethon Institute for Gene Therapy, H. San Raffaele Scientific Institute, Milan, Italy; Vita Salute University, H. San Raffaele Scientific Institute, Milan, Italy Laboratory of Gene Transfer and Therapy, Institute for Cancer Research and Treatment (IRCC), University of Torino, Turin, Italy; HSR-Telethon Institute for Gene Therapy, H. San Raffaele Scientific Institute, Milan, Italy; Vita Salute University, H. San Raffaele Scientific Institute, Milan, Italy * Corresponding author; email: naldini.luigi{at}hsr.it. Stable gene replacement by in vivo administration of Lentiviral Vectors (LV) has therapeutic potential for metabolic disorders and other systemic diseases. We studied the expression of intracellular and secreted proteins by LV in immunocompetent mice. Liver, spleen and bone marrow cells were efficiently transduced. However, transgene expression, driven by an ubiquitous promoters, was limited by transgene-specific cellular and humoral immune responses leading to the clearance of transduced cells. After GFP gene transfer, the liver showed infiltration of CD8+ cytotoxic T cells, and GFP-specific CD8+ T cells were isolated from the spleen. After human Factor IX (h.FIX) gene transfer, anti-h.FIX antibodies were induced. These immune responses were not detected in mice injected with heat-inactivated or genome-lacking LV, or in GFP-transgenic mice, indicating that they were specifically triggered by transgene expression in vivo. Intriguingly, selective targeting of LV expression to hepatocytes limited the immune responses to the transgenes. By this approach, high levels of h.FIX, potentially in the therapeutic range, were reached and maintained long-term in immunocompetent mice, without inducing antibody formation. These results prompt further studies in relevant animal models to explore the potential of in vivo LV administration for the gene therapy of hemophilias and other liver-based diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Lentiviral vector for hemophilia gene therapy Roland W. Herzog Blood 2004 103: 3609-3610. [Full Text] [PDF] This article has been cited by other articles: H. Matsui, M. Shibata, B. Brown, A. 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