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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2797-2805. Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-10-049312. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-10-049312v1 blood-2006-10-049312v2 109/7/2797    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 Brown, B. D. Articles by Naldini, L. Search for Related Content PubMed PubMed Citation Articles by Brown, B. D. Articles by Naldini, L. Related Collections Immunobiology Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance Brian D. Brown1, Giovanni Sitia2, Andrea Annoni1, Ehud Hauben1, Lucia Sergi Sergi1, Anna Zingale1, Maria Grazia Roncarolo1,3, Luca G. Guidotti2,4, and Luigi Naldini1,3 1 San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; 2 Immunopathogenesis of Liver Infections Unit, San Raffaele Scientific Institute, Milan, Italy; 3 Vita Salute San Raffaele University, Milan, Italy; 4 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LVs) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into nondividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared with nonparenchymal cells, and the duration of transgene expression is often limited by immune responses. Here, we investigated the role of innate antiviral responses in these events. We show that administration of LVs to mice triggers a rapid and transient IFNß response. This effect was dependent on functional vector particles, and in vitro challenge of antigen-presenting cells suggested that plasmacytoid dendritic cells initiated the response. Remarkably, when LVs were administered to animals that lack the capacity to respond to IFNß, there was a dramatic increase in hepatocyte transduction, and stable transgene expression was achieved. These findings indicate that, even in the setting of acute delivery of replication-defective vectors, IFNs effectively interfere with transduction in a cell-type–specific manner. Moreover, because disabling a single component of the innate/immune network was sufficient to establish persistent xenoantigen expression, our results raise the hope that the immunologic barriers to gene therapy are less insurmountable than expected. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Interferon limits lentiviral vectors in the liver Roland W. Herzog Blood 2007 109: 2670-2671. [Full Text] [PDF] This article has been cited by other articles: B. D. Brown, A. Cantore, A. Annoni, L. S. Sergi, A. Lombardo, P. Della Valle, A. D'Angelo, and L. Naldini A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice Blood, December 15, 2007; 110(13): 4144 - 4152. [Abstract] [Full Text] [PDF]

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