Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Transduction Properties of an Adenovirus Vector Containing Sequences Complementary to a Liver-Specific microRNA, miR-122a, in the 3′-Untranslated Region of the E4 Gene in Human Hepatocytes from Chimeric Mice with Humanized Liver
Fuminori Sakurai , Tomohito Tsukamoto, Ryosuke Ono, Fumitaka Nishimae, Aoi Shiota, Shunsuke Iizuka, Kahori Shimizu, Eiko Sakai, Yuji Ishida, Chise Tateno, Kazuaki Chayama, Hiroyuki Mizuguchi
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Keywords: adenovirus vector, primary human hepatocyte, cytotoxicity, transduction
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2021 Volume 44 Issue 10 Pages 1506-1513

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Abstract

Replication-incompetent adenovirus (Ad) vectors are promising gene delivery vehicles, especially for hepatocytes, due to their superior hepatic tropism; however, in vivo application of an Ad vector often results in hepatotoxicity, mainly due to the leaky expression of Ad genes from the Ad vector genome. In order to reduce the Ad vector-induced hepatotoxicity, we previously developed an Ad vector containing the sequences perfectly complementary to a liver-specific microRNA (miRNA), miR-122a, in the 3′-untranslated region (UTR) of the E4 gene. This improved Ad vector showed a significant reduction in the leaky expression of Ad genes and hepatotoxicity in the mouse liver and primary mouse hepatocytes; however, the safety profiles and transduction properties of this improved Ad vector in human hepatocytes remained to be elucidated. In this study, we examined the transgene expression and safety profiles of Ad vectors with miR-122a-targeted sequences in the 3′-UTR of the E4 gene in human hepatocytes from chimeric mice with humanized liver. The transgene expression levels of Ad vectors with miR-122a-targeted sequences in the 3′-UTR of the E4 gene were significantly higher than those of the conventional Ad vectors. The leaky expression levels of Ad genes of Ad vectors with miR-122a-targeted sequences in the 3′-UTR of the E4 gene in the primary human hepatocytes were largely reduced, compared with the conventional Ad vectors, resulting in an improvement in Ad vector-induced cytotoxicity. These data indicated that this improved Ad vector was a superior gene delivery vehicle without severe cytotoxicity for not only mouse hepatocytes but also human hepatocytes.

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