MicroRNA Regulation of Tumor-Destroying Viruses Avoids Unwanted Viral Pathology

Scientists have determined how to produce replication-competent viruses with key toxicities removed, providing a new platform for development of improved cancer treatments and better vaccines for a wide array of viral diseases.

Cellular microRNA molecules regulate the stability of mRNA in different cell types, and this newly understood mechanism provides the possibility to modify viruses for cell-specific inactivation. Cancer Research UK (London) scientists from the University of Oxford (UK), with support from colleagues at Vrije Universities (Amsterdam, The Netherlands), reported that this approach can be used to regulate proliferation of adenovirus in a study published May 22, 2009, in the open-access journal PLoS Pathogens.

Adenovirus is a DNA virus widely used in cancer therapy but which causes hepatic disease in mice. Oxford professor Len Seymour and colleagues found that introducing sites into the virus genome that are recognized by microRNA 122 leads to hepatic degradation of significant viral mRNA, thereby lessening the virus' ability to adversely affect the liver, while maintaining its ability to replicate in and kill tumor cells.

Tumor-killing replicating viruses are a hot topic in the biotherapeutics arena, with many clinical trials ongoing worldwide. That Prof. Seymour's team set out to and has now defined a process whereby wild type virus potency could be maintained in tumor cells but the virus could be switched off in tissues vulnerable to pathology adds important information to the current base of knowledge.

"This approach is surprisingly effective and quite versatile. It could find a range of applications in controlling the activity of therapeutic viruses, both for cancer research and also to engineer a new generation of conditionally-replicating vaccines, where the vaccine pathogen is disabled in its primary sites of toxicity,” Prof. Seymour noted.

This study was intended chiefly to examine and demonstrate the potential of this new mechanism to regulate virus activity, according to the investigators. Although the current tumor-killing virus is useful in mice, transfer of the technology into the clinical environment will require reengineering of the virus to overcome virus pathologies seen in humans, and it will be at least two years before this can be tested in the clinics.

Cancer Research UK is UK's leading cancer charity.

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