Fiber-modified adenovirus vectors decrease liver toxicity through reduced IL-6 production.
Adenovirus (Ad) vectors are one of the most commonly used viral vectors in gene therapy clinical trials. However, they elicit a robust innate immune response and inflammatory responses. Improvement of the therapeutic index of Ad vector gene therapy requires elucidation of the mechanism of Ad vector-induced inflammation and cytokine/chemokine production as well as development of the safer vector. In the present study, we found that the fiber-modified Ad vector containing poly-lysine peptides in the fiber knob showed much lower serum IL-6 and aspartate aminotransferase levels (as a maker of liver toxicity) than the conventional Ad vector after i.v. administration, although the modified Ad vector showed higher transgene production in the liver than the conventional Ad vector. RT-PCR analysis showed that spleen, not liver, is the major site of cytokine, chemokine, and IFN expression. Splenic CD11c(+) cells were found to secret cytokines. The tissue distribution of Ad vector DNA showed that spleen distribution was much reduced in this modified Ad vector, reflecting reduced IL-6 levels in serum. Liver toxicity by the conventional Ad vector was reduced by anti-IL-6R Ab, suggesting that IL-6 signaling is involved in liver toxicity and that decreased liver toxicity of the modified Ad vector was due in part to the reduced IL-6 production. This study contributes to an understanding of the biological mechanism in innate immune host responses and liver toxicity toward systemically administered Ad vectors and will help in designing safer gene therapy methods that can reduce robust innate immunity and inflammatory responses.
Koizumi
Naoya
N
Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan.
Yamaguchi
Tomoko
T
Kawabata
Kenji
K
Sakurai
Fuminori
F
Sasaki
Tomomi
T
Watanabe
Yoshiteru
Y
Hayakawa
Takao
T
Mizuguchi
Hiroyuki
H
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D004796:Clinical Enzyme Tests; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics; D005822:Genetic Vectors / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D007113:Immunity, Innate; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood; D008107:Liver Diseases / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011107:Polylysine / Q000494:pharmacology*; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
D016207:Cytokines; D015850:Interleukin-6; D011107:Polylysine; D001219:Aspartate Aminotransferases