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: 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
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 6 Pg. 1097-106 (Jun 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21468006 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MicroRNAs

Topics

• Animals
• Brain Neoplasms (therapy)
• Cell Line
• Cell Line, Tumor
• Cell Survival (genetics, physiology)
• Chlorocebus aethiops
• Female
• Genetic Vectors (genetics)
• Glioblastoma (therapy)
• Glioma (therapy)
• Humans
• Immunoblotting
• In Vitro Techniques
• Measles virus (genetics, physiology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (genetics)
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics, physiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Vero Cells
• Xenograft Model Antitumor Assays