Fibroblast growth factor 2 retargeted adenovirus has redirected cellular tropism: Evidence for reduced toxicity and enhanced antitumor activity in mice

Adenovirus (Ad) have been used as vectors to deliver genes to a wide variet y of tissues. Despite achieving high expression levels in vivo, Ad vectors display normal tissue toxicity, transient expression, and antivector immune responses that limit therapeutic potential. To circumvent these problems, several retargeting strategies to abrogate native tropism and redirect Ad u ptake through defined receptors have been attempted. Despite success in cel l culture, in vivo results have generally not shown sufficient selectivity for target tissues. We have previously identified (C. K. Goldman st al., Ca ncer Res.,57: 1447-1451, 1997) the fibroblast growth factor (FGF) ligand an d receptor families as conferring sufficient specificity and binding affini ty to be useful for targeting DNA in vivo. In the present studies, we retar geted Ad using basic:FGF (FGF2) as a targeting ligand; Cellular uptake is r edirected through high-affinity FGF receptors (FGFRs) and not the more ubiq uitous lower-affinity Ad receptors. Initial in vitro :experiments demonstra ted a 10- to 100-fold increase in gene expression in numerous FGFR positive -(FGFR(+)) cell lines using FGF2-Ad when compared with Ad. To determine whe ther increased selectivity could be detected in vivo, FGF2-Ad was administe red i.v. to normal mice. FGF2-Ad demonstrates markedly decreased hepatic to xicity and liver transgene expression compared with Ad treatment. Important ly, FGF2-Ad encoding the herpes simplex virus thymidine kinase (TK) gene tr ansduces Ed-resistant FGFR(+) tumor cells both ex vivo and in vivo, which r esults in substantially enhanced survival (180-260%) when the prodrug ganci covir is: administered. Because FGFRs are up-regulated on many types of mal ignant or injured cells, this broadly useful method to redirect native Ad t ropism and to increase the potency of gene expression may offer significant therapeutic advantages.