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Adenoviral Expression of Suppressor of Cytokine Signaling-1 Reduces Adenovirus Vector-Induced Innate Immune Responses¹

Haruna Sakurai^*,, Katsuhisa Tashiro^*,, Kenji Kawabata^*, Tomoko Yamaguchi^*,, Fuminori Sakurai^*, Shinsaku Nakagawa and Hiroyuki Mizuguchi^2,*,

^* Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; and Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

Adenovirus (Ad) vectors are among the most commonly used viral vectors in gene therapy clinical trials. However, the application of Ad vectors has been limited to local injection in many cases, because the systemic administration of Ad vectors triggers innate immune responses such as inflammatory cytokine production and tissue damage. To overcome this limitation, it will be necessary to develop safer Ad vectors less likely to induce the innate immune response. In the present study, we demonstrated that a suppressor of cytokine signaling-1 (SOCS1)-expressing Ad vector, Ad-SOCS1, reduces the innate immune response induced by Ad vectors. RAW264.7-SOCS1, a macrophage-like cell line that stably expresses SOCS1, was shown to produce lower levels of inflammatory cytokines after the transduction of Ad vectors. The systemic administration of Ad-SOCS1 into mice elicited the reduced production of inflammatory cytokines, as compared with that elicited by control Ad vectors, i.e., luciferase-expressing Ad vector, Ad-L2. Furthermore, the coadministration of Ad-L2 with Ad-SOCS1 attenuated inflammatory cytokine production and liver toxicity as compared with injection with Ad-L2 alone, and this was achieved without the suppression of luciferase production in various organs. The JAK/STAT pathway was involved in Ad vector-mediated cytokine production, which was impaired by the overexpression of SOCS1. These findings indicate that Ad-SOCS1 could be useful for reducing Ad vector-mediated innate immunity.

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. T.Y. is the Research Fellow of the Japan Society for the Promotion of Science.

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

³ Abbreviations used in this paper: Ad, adenovirus; DC, dendritic cell; cDC, conventional DC; SOCS1, suppressor of cytokine signaling-1; GPT, glutamate pyruvate transaminase; VP, viral particle; DN, dominant negative; KO, knockout; pDC, plasmacytoid DC.