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* Amgen, Inc., Thousand Oaks, California 91320, USA; and Selective Genetics, Inc., San Diego, California 92121, USA
1Correspondence: Selective Genetics, Inc., 11035Roselle St., San Diego, CA 92121, USA. E-mail: jdoukas{at}selectivegenetics.com
A major goal of gene therapy is to improve target specificity by
delivering vectors through alternative cellular receptors. We
previously reported that adenoviral vector delivery through basic
fibroblast growth factor (FGF2) receptors enhances both cellular
transduction and in vivo efficacy. We now present
studies addressing the cellular pathways and mechanisms underlying
these events. Cellular receptors for adenoviruses are not required for
transduction by FGF2-retargeted vectors. Moreover, 
V
integrins can antagonize FGF2 retargeting, in contrast to their
obligatory role in non-retargeted vector delivery. By contrast,
high-affinity FGF receptors, which are overexpressed on potential tumor
targets, are required for FGF2-retargeted transduction. Low-affinity
heparan sulfate proteoglycan interactions, however, are not a
prerequisite, in marked contrast to their obligatory role in FGF2
mitogenic signaling. By comparing receptor expression and ligand
binding with transgene expression, we also demonstrate that FGF2
retargeting enhances transduction by mechanisms other than increasing
the number of targeted cells. Rather, the use of alternative targeting
ligands supports the conclusion that specific receptor interactions and
intracellular events serve to enhance transgene expression. Together,
these studies highlight the unique delivery and transduction pathways
used by FGF2-retargeted adenoviruses, and help define the basis for
their enhanced in vivo efficacy.—Doukas, J., Hoganson,
D. K., Ong, M., Ying, W., Lacey, D. L., Baird, A., Pierce,
G. F., Sosnowski, B. A. Retargeted delivery of adenoviral
vectors through fibroblast growth factor receptors involves unique
cellular pathways.
Key Words: gene therapy • cancer • integrin • affinity
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