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- Title
MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism.
- Authors
Leber, Mathias F; Bossow, Sascha; Leonard, Vincent H J; Zaoui, Karim; Grossardt, Christian; Frenzke, Marie; Miest, Tanner; Sawall, Stefanie; Cattaneo, Roberto; von Kalle, Christof; Ungerechts, Guy
- 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.
- Publication
Molecular therapy : the journal of the American Society of Gene Therapy, 2011, Vol 19, Issue 6, p1097
- ISSN
1525-0024
- Publication type
Journal Article
- DOI
10.1038/mt.2011.55