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Mol Ther. 2010 Aug;18(8):1440-9. doi: 10.1038/mt.2010.103. Epub 2010 Jun 15.

Identification of genetically modified Maraba virus as an oncolytic rhabdovirus.

Author information

1
Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.

Abstract

To expand our current array of safe and potent oncolytic viruses, we screened a variety of wild-type (WT) rhabdoviruses against a panel of tumor cell lines. Our screen identified a number of viruses with varying degrees of killing activity. Maraba virus was the most potent of these strains. We built a recombinant system for the Maraba virus platform, engineered a series of attenuating mutations to expand its therapeutic index, and tested their potency in vitro and in vivo. A double mutant (MG1) strain containing both G protein (Q242R) and M protein (L123W) mutations attenuated Maraba virus in normal diploid cell lines, yet appeared to be hypervirulent in cancer cells. This selective attenuation was mediated through interferon (IFN)-dependent and -independent mechanisms. Finally, the Maraba MG1 strain had a 100-fold greater maximum tolerable dose (MTD) than WT Maraba in vivo and resulted in durable cures when systemically administered in syngeneic and xenograft models. In summary, we report a potent new oncolytic rhabdovirus platform with unique tumor-selective attenuating mutations.

PMID:
20551913
PMCID:
PMC2927055
DOI:
10.1038/mt.2010.103
[Indexed for MEDLINE]
Free PMC Article
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