MicroRNA-mediated multi-tissue detargeting of oncolytic measles virus
| Autor: | M A Baertsch, Sascha Bossow, M Singh, Jessica Albert, Mathias F. Leber, Christine E. Engeland, Guy Ungerechts, C von Kalle, Christian Grossardt, Dirk Jäger |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Cell Survival Genetic Vectors Molecular Sequence Data Gene Expression Virus Replication Cell Line Measles virus Mice Transduction (genetics) Cytopathogenic Effect Viral Genes Reporter Transduction Genetic RNA interference Cell Line Tumor Neoplasms Chlorocebus aethiops Gene Order microRNA Animals Humans Vector (molecular biology) Vero Cells Molecular Biology Tropism Base Sequence biology biology.organism_classification Xenograft Model Antitumor Assays Virology Oncolytic virus Disease Models Animal MicroRNAs Oncolytic Viruses Gene Knockdown Techniques Systemic administration Cancer research Molecular Medicine Female RNA Interference |
| Zdroj: | Cancer Gene Therapy. 21:373-380 |
| ISSN: | 1476-5500 0929-1903 |
| Popis: | Precise oncotropism is required for successful systemic administration of next-generation oncolytic measles viruses (MVs). We have previously established a system for efficient post-entry targeting by insertion of synthetic microRNA target sites (miRTS) into the MV genome, thereby repressing replication in the presence of cognate microRNAs. Thus, differential expression of microRNAs, as frequently observed in normal compared with malignant tissues, can be exploited to increase vector specificity and safety. Here we report the combination of miRTS for different microRNAs in a single vector to detarget pivotal organs at risk during systemic administration (liver, brain, gastrointestinal tract). Accordingly, miRTS for miR-122, miR-7 and miR-148a that are enriched in these tissues were inserted to create multi-tissue-detargeted MV (MV-EGFP(mtd)). Replication of MV-EGFP(mtd) is repressed in cell lines as well as in non-transformed primary human hepatocytes and liver slices expressing cognate microRNAs. Oncolytic potency of MV-EGFP(mtd) is retained in a model of pancreatic cancer in vitro and in vivo. This work is a proof-of-concept that favorable expression profiles of multiple microRNAs can be exploited concomitantly to reshape the tropism of MV without compromising oncolytic efficacy. This strategy can be adapted to different vectors and cancer entities for safe and efficient high-dose systemic administration in clinical trials. |
| Databáze: | OpenAIRE |
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