title: MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism.
abstract: Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased tumor-cell specificity, and are currently under investigation in clinical trials including a phase I study for glioblastoma multiforme (GBM). Recent preclinical studies have shown that the cellular tropism of several viruses can be controlled by inserting microRNA-target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. Since neuron-specific microRNA-7 is downregulated in gliomas but highly expressed in normal brain tissue, we engineered a microRNA-sensitive virus containing target sites for microRNA-7 in the 3'-untranslated region of the viral fusion gene. In presence of microRNA-7 this modification inhibits translation of envelope proteins, restricts viral spread, and progeny production. Even though highly attenuated in presence of microRNA-7, this virus retained full efficacy against glioblastoma xenografts. Furthermore, microRNA-mediated inhibition protected genetically modified mice susceptible to MV infection from a potentially lethal intracerebral challenge. Importantly, endogenous microRNA-7 expression in primary human brain resections tightly restricted replication and spread of microRNA-sensitive virus. This is proof-of-concept that tropism restriction by tissue-specific microRNAs can be adapted to oncolytic MV to regulate viral replication and gene expression to maximize tumor specificity without compromising oncolytic efficacy.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mathias F
authors.initials: MF
authors.lastname: Leber
authors.forename: Sascha
authors.initials: S
authors.lastname: Bossow
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: Leonard
authors.forename: Karim
authors.initials: K
authors.lastname: Zaoui
authors.forename: Christian
authors.initials: C
authors.lastname: Grossardt
authors.forename: Marie
authors.initials: M
authors.lastname: Frenzke
authors.forename: Tanner
authors.initials: T
authors.lastname: Miest
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sawall
authors.forename: Roberto
authors.initials: R
authors.lastname: Cattaneo
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Guy
authors.initials: G
authors.lastname: Ungerechts
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D002522:Chlorocebus aethiops; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000628:therapy; D005910:Glioma / Q000628:therapy; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008459:Measles virus / Q000235:genetics* / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs