Fibroblast growth factor 2-retargeted adenoviral vectors exhibit a modified biolocalization pattern and display reduced toxicity relative to native adenoviral vectors

Targeted vectors provide a number of advantages for systemic and local gene delivery strategies. Several groups have investigated the utility of using various ligands to alter the tropism of adenovirus (Ad) vectors. We have p reviously demonstrated that fibroblast growth factor (FGF) ligands can spec ifically target DNA transfection and Ad transduction through high-affinity FGF receptors (FGFRs), FGFRs are overexpressed in abnormally proliferating tissues, such as malignancies. The present studies explore the effects of r etargeting with FGF2 on the tissue localization pattern and the systemic to xicity of Ad in mice, Results of semiquantitative PCR analyses indicate tha t the distribution of FGF2-Ad vector genome sequences after intravenous adm inistration in mice is altered, Markedly lower amounts (10- to 20-fold) of FGF2-Ad localize to the liver when compared with native Ad, This decrease i n liver deposition translates into a significant reduction in subsequent to xicity as measured by serum transaminases and histopathology in mice inject ed with FGF2-Ad-HSV-thymidine kinase with and without ganciclovir administr ation, In an intraperitoneal model of ovarian cancer, FGF2-Ad generates inc reased transgene expression in tumor tissue when compared with Ad, Taken to gether, these results indicate that the retargeting of Ad with FGF2 results in a more efficient vector system for systemic and regional gene therapy a pplications, with concomitant lower levels of systemic toxicity.