Sexual HealthMicroRNA Regulation Of Tumor-killing 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 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 in a study published May
22
in the open-access journal PLoS Pathogens.
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.
Financial Disclosure: RC and FC are supported by Cancer Research UK
(http://www.cancer.org.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.
Citation:
"Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells."
Cawood R, Chen HH, Carroll F, Bazan-Peregrino M, van Rooijen N, et al. (2009)
PLoS Pathog 5(5): e1000440.
PLoS Pathogens