title: Attenuation of vesicular stomatitis virus encephalitis through microRNA targeting.
abstract: Vesicular stomatitis virus (VSV) has long been regarded as a promising recombinant vaccine platform and oncolytic agent but has not yet been tested in humans because it causes encephalomyelitis in rodents and primates. Recent studies have shown that specific tropisms of several viruses could be eliminated by engineering microRNA target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. We therefore sought to determine whether microRNA targets could be engineered into VSV to ameliorate its neuropathogenicity. Using a panel of recombinant VSVs incorporating microRNA target sequences corresponding to neuron-specific or control microRNAs (in forward and reverse orientations), we tested viral replication kinetics in cell lines treated with microRNA mimics, neurotoxicity after direct intracerebral inoculation in mice, and antitumor efficacy. Compared to picornaviruses and adenoviruses, the engineered VSVs were relatively resistant to microRNA-mediated inhibition, but neurotoxicity could nevertheless be ameliorated significantly using this approach, without compromise to antitumor efficacy. Neurotoxicity was most profoundly reduced in a virus carrying four tandem copies of a neuronal mir125 target sequence inserted in the 3'-untranslated region of the viral polymerase (L) gene.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kelly
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nace
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D006224:Cricetinae; D017931:DNA Primers; D015536:Down-Regulation / Q000235:genetics; D018792:Encephalitis, Viral / Q000628:therapy* / Q000821:virology; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018116:Vesiculovirus / Q000302:isolation & purification* / Q000472:pathogenicity / Q000502:physiology; D014779:Virus Replication
chemical_list: D017931:DNA Primers; D035683:MicroRNAs