MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism

Mathias F. Leber, Sascha Bossow, Vincent H.J. Leonard, Karim Zaoui, Christian Grossardt, Marie Frenzke, Tanner Miest, Stefanie Sawall, Roberto Cattaneo, Christof Von Kalle, Guy Ungerechts

Research output: Contribution to journalArticle

68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1097-1106
Number of pages10
JournalMolecular Therapy
Volume19
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Leber, M. F., Bossow, S., Leonard, V. H. J., Zaoui, K., Grossardt, C., Frenzke, M., Miest, T., Sawall, S., Cattaneo, R., Von Kalle, C., & Ungerechts, G. (2011). MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism. Molecular Therapy, 19(6), 1097-1106. https://doi.org/10.1038/mt.2011.55