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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.


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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 IFN{alpha}ß 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 IFN{alpha}ß, 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.


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Related Article in Blood Online:

Interferon limits lentiviral vectors in the liver
Roland W. Herzog
Blood 2007 109: 2670-2671. [Full Text] [PDF]



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