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Fiber-Modified Adenovirus Vectors Decrease Liver Toxicity through Reduced IL-6 Production¹

Naoya Koizumi^*,, Tomoko Yamaguchi^*, Kenji Kawabata^*, Fuminori Sakurai^*, Tomomi Sasaki^*, Yoshiteru Watanabe, Takao Hayakawa and Hiroyuki Mizuguchi^2,*,

^* Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Osaka, Japan; Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo, Japan; Pharmaceuticals and Medical Devices Agency, Tokyo, Japan; and Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Ministry of Health, Labor, and Welfare of Japan.

² Address correspondence and reprint requests to Dr. Hiroyuki Mizuguchi, Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Asagi 7-6-8, Saito, Ibaraki, Osaka 567-0085, Japan. E-mail address: mizuguch{at}nibio.go.jp

³ Abbreviations used in this paper: Ad, adenovirus; AST, aspartate aminotransferase; CAR, coxsackievirus and Ad receptor; DC, dendritic cell; HSG, heparan sulfate glycosaminoglycan; PEG, polyethylene glycol; VP, virus particle.

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