ENHANCEMENT OF IN-VIVO ADENOVIRUS-MEDIATED GENE-TRANSFER AND EXPRESSION BY PRIOR DEPLETION OF TISSUE MACROPHAGES IN THE TARGET ORGAN

Based on the hypothesis that tissue macrophages present an obstacle fo r adenovirus (Ad) vector-mediated gene transfer to internal organs, th is study evaluated the consequences of transient depletion of Kupffer cells on subsequent transfer of the Ad vector genome and Ad vector-dir ected gene expression in the livers of experimental animals. Depletion of Kupffer cells in mice by intravenous administration of multilamell ar liposomes containing dichloromethylene-bisphosphonate permitted sub sequent intravenous administration of an Ad vector to provide a higher input of recombinant adenoviral DNA to the liver, an absolute increas e in transgene expression, and a delayed clearance of the vector DNA a nd transgene expression. These observations suggest that the tissue ma crophages pose a significant hurdle to Ad vector-mediated gene transfe r and that strategies to transiently suppress macrophage defenses migh t be useful in enhancing the efficiency of this in vivo gene transfer system.