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 for adenovirus (Ad) vector-mediated gene transfer to internal organs, this study evaluated the consequences of transient depletion of Kupffer cells on subsequent transfer of the Ad vector genome and Ad vector-directed gene expression in the livers of experimental animals. Depletion of Kupffer cells in mice by intravenous administration of multilamellar liposomes containing dichloromethylene-bisphosphonate permitted subsequent intravenous administration of an Ad vector to provide a higher input of recombinant adenoviral DNA to the liver, an absolute increase in transgene expression, and a delayed clearance of the vector DNA and transgene expression. These observations suggest that the tissue macrophages pose a significant hurdle to Ad vector-mediated gene transfer and that strategies to transiently suppress macrophage defenses might be useful in enhancing the efficiency of this in vivo gene transfer system.
Wolff
G
G
Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center, New York, New York 10021, USA.
Worgall
S
S
van Rooijen
N
N
Song
W R
WR
Harvey
B G
BG
Crystal
R G
RG
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007728:Kupffer Cells / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019076:Transgenes