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 previously demonstrated that fibroblast growth factor (FGF) ligands can specifically 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 retargeting with FGF2 on the tissue localization pattern and the systemic toxicity of Ad in mice. Results of semiquantitative PCR analyses indicate that the distribution of FGF2-Ad vector genome sequences after intravenous administration 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 in liver deposition translates into a significant reduction in subsequent toxicity as measured by serum transaminases and histopathology in mice injected with FGF2-AdHSV-thymidine kinase with and without ganciclovir administration. In an intraperitoneal model of ovarian cancer, FGF2-Ad generates increased transgene expression in tumor tissue when compared with Ad. Taken together, these results indicate that the retargeting of Ad with FGF2 results in a more efficient vector system for systemic and regional gene therapy applications, with concomitant lower levels of systemic toxicity.
Printz
M A
MA
Selective Genetics, Inc., San Diego, CA 92121, USA. mprintz@selectivegenetics.com
Gonzalez
A M
AM
Cunningham
M
M
Gu
D L
DL
Ong
M
M
Pierce
G F
GF
Aukerman
S L
SL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D015774:Ganciclovir / Q000494:pharmacology; D018390:Gene Targeting; D005822:Genetic Vectors / Q000009:adverse effects; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism; D016133:Polymerase Chain Reaction; D019076:Transgenes
D017931:DNA Primers; D016222:Fibroblast Growth Factor 2; D015774:Ganciclovir