May 25, 2009 Scientists at Oxford University have tamed a virus so that it attacks and destroys cancer cells but does not harm healthy cells. They 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 broad range of viral diseases.
Cellular microRNA molecules regulate the stability of mRNA in different cell types, and this newly-understood mechanism provides the possibility to engineer viruses for cell-specific inactivation. Cancer Research UK scientists at the University of Oxford, United Kingdom, with support from colleagues at Vrije Universiteit, Amsterdam, report that this approach can be used to regulate proliferation of adenovirus.
Adenovirus is a DNA virus widely used in cancer therapy but which causes hepatic disease in mice. Professor Len Seymour and colleagues found that introducing sites into the virus genome that are recognized by microRNA 122 leads to hepatic degradation of important viral mRNA, thereby diminishing 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 Professor Seymour's group set out to and has now defined a mechanism whereby wild type virus potency could be maintained in tumor cells but the virus could be 'turned 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," Professor Seymour says.
The present study was intended mainly to explore and demonstrate the potential of this new mechanism to regulate virus activity. Although the current tumor-killing virus is useful in mice, transfer of the technology into the clinical setting will require re-engineering 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.
Modified naturally-occurring viruses have already had important uses in medicine including their use as vaccines, notably for measles, mumps, polio, influenza, and chicken pox. They have already been developed as potential cancer-killing therapies, in an approach called virotherapy.
RC and FC are supported by Cancer Research UK; HC by a research studentship from the New Zealand Government, and MB by a Bellhouse Foundation Fellowship (Magdalen College, Oxford). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist.
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- Ryan Cawood, Hannah H. Chen, Fionnadh Carroll, Miriam Bazan-Peregrino, Nico van Rooijen, Leonard W. Seymour. Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells. PLoS Pathog, 5(5): e1000440 DOI: 10.1371/journal.ppat.1000440
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