Development of a next-generation adenovirus vector containing miRNA-mediated post-transcriptional gene silencing system and elucidation of adenovirus vector-induced hepatotoxicity

Abstract

Systemic administration of an adenovirus (Ad) vector often causes hepatotoxicity. The E1 gene, which is crucial for the transcription of other Ad genes, is deleted from Ad vector genome. Theoretically, Ad genes should not be expressed by deletion of the E1 gene; however, Ad genes are slightly expressed from Ad vector genome, resulting in hepatotoxicity. In order to suppress the leaky expression of Ad genes, complementary sequences for liver-specific miR-122a were inserted into the 3’-untranslated region (UTR) of the Ad genes in the Ad vector genome. The Ad vector containing miR-122a-targeted sequences in the 3’-UTR of the E4 gene mediated efficient transduction without severe hepatotoxicity.