title: Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability.
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.
  
  
  RESULTS
  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 toxicity in mice while Ad[CgA-E1A-miR122] injections did not. Furthermore, a miR122-detargeted adenovirus with the wild-type E1A promoter showed reduced replication in hepatic cells compared to wild-type Ad5 but not to the same extent as the miR122-detargeted adenovirus with the neuroendocrine-selective CgA promoter.
  
  
  CONCLUSIONS
  A combination of transcriptional (promoter) and post-transcriptional (miRNA target) regulation to control virus replication may allow for the use of higher doses of adenovirus for efficient tumors treatment without liver toxicity.
authors.affiliation: Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Justyna
authors.initials: J
authors.lastname: Leja
authors.forename: Berith
authors.initials: B
authors.lastname: Nilsson
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gustafson
authors.forename: Göran
authors.initials: G
authors.lastname: Akerström
authors.forename: Kjell
authors.initials: K
authors.lastname: Oberg
authors.forename: Valeria
authors.initials: V
authors.lastname: Giandomenico
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013269:Stochastic Processes
chemical_list: D000970:Antineoplastic Agents