MicroRNA regulation of tumor-killing viruses
Attenuated viruses have found important applications in medicine, including their use as vaccines (notably for measles, mumps, polio, influenza, and chicken pox) and their experimental development as selective cancer-killing agents, so-called “virotherapy”. Wild-type versions are often most effective in both of these settings; however, attenuated viruses have usually been developed to decrease the risk of significant viral pathology. Recent advances in understanding regulation of gene expression by microRNA now afford the possibility to design viruses that are “selectively attenuated” in sites of potential pathology, by engineering them for inhibition by micro-RNA molecules that are expressed there. A new paper describes how researchers have engineered wild-type adenovirus for recognition by a microRNA expressed in hepatocytes, producing a virus that retains wild-type infection and replication at sites of therapeutic activity (such as cancer cells) but is severely attenuated in hepatocytes, both in vitro and in vivo. This virus caused no significant liver toxicity to mice even when applied at ten times the lethal dose of wild-type virus. The ability to produce replication-competent viruses with key toxicities removed should provide a new platform for development of improved cancer treatments and better vaccines for a broad range of virus 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. Adenovirus is a DNA virus widely used in cancer therapy but which causes hepatic disease in mice. Researchers 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. They have 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. 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.
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
Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 39 UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (561010 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral diseases.
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Tags: adenovirus, Biology, Biotechnology, cancer, Health, Medicine, Microbiology, Science, Vaccines, Virology, virotherapy, virus
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