double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing abilitydouble-detargeted溶瘤腺病毒显示肝细胞中复制逮捕和保留神经内分泌细胞死亡的能力.pdfVIP

Double-Detargeted Oncolytic Adenovirus Shows Replication Arrest in Liver Cells and Retains Neuroendocrine Cell Killing Ability 1 1 1 2 ¨ ˚ ¨ 3 ¨ 4 Justyna Leja , Berith Nilsson , Di Yu , Elisabet Gustafson , Goran Akerstrom , Kjell Oberg , Valeria Giandomenico4, Magnus Essand 1* 1 Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, 2 Department of Women’s and Children’s Health, University Hospital, Uppsala, Sweden, 3 Department of Surgical Sciences, University Hospital, Uppsala, Sweden, 4 Department of Medical Sciences, University Hospital, Uppsala, Sweden Abstract Background: We have previously developed an oncolytic serotype 5 adenovirus (Ad5) with chromogranin-A (CgA) promoter-controlled E1A expression, Ad[CgA-E1A], with the intention to treat neuroendocrine tumors, including carcinoids. Since carcinoids tend to metastasize to the liver it is important to fully repress viral replication in hepatocytes to avoid adenovirus-related liver toxicity. Herein, we explore miRNA-based regulation of E1A expression as a complementary mechanism to promoter-based transcriptional control. Methodology/Principal Findings: Ad[CgA-E1A-miR122], where E1A expression is further controlled by six tandem repeats of the target sequence for the liver-specific miR122, was constructed and compared to Ad[CgA-E1A]. We observed E1A suppression and replication arrest of the miR122-detargeted adenovirus in normal hepatocytes, while the two viruses killed carcinoid cells to the same degree. Repeated intravenous injections of Ad[CgA-E1A] induced liver