Oncolytic viruses

Oncolytic viruses(OVs) are viruses that are genetically engineered to preferentially replicate in tumour cells while sparing normal cells. Oncolysis results from viral replication and subsequent cell lysis.

The mechanisms by which preferential oncolysis is thought to occur, are as follows:

• Deleting or inactivating genes that are required for replication in normal cells but not tumour cells(ex: DNA replication enzymes)
• Using tumour specific promoters for key viral genes
• Engineering viral tropism for tumour cells

Now the idea for using viruses to treat tumours has been around for a long time. In fact, the first recorded case of a virus improving the symptoms of a tumour, is from 1904. The reference is listed in the Papers section of the website and is definitely worth a look. Prof. Dock, who was the Professor of Medicine at the University of Michigan noticed that his 42 year old patient with myelogenous leukemia, had improving symptoms and white cell count, during a bout of influenza. Once she recovered from her influenza, her leukemia worsened.

In the decades that followed various viruses were used in attempts to battle tumours but without the ability to accurately manipulate viruses genetically, the results remained disappointing. However, in 1991 almost a 90 years after Dock's paper, a study was published on a genetically engineered virus which preferentially infected and lysed tumour cells. The virus used was a strain of herpes simplex virus (HSV) with a deletion in the gene coding for thymidine kinase (TK). TK is involved in viral DNA synthesis. HSV commonly infects neuronal cells where DNA synthesis is not occuring and having its own TK allows HSV to efficiently replicate.

Deleting TK renders the virus less able to replicate in normal tissues. In tumours however, where TK is upregulated, virus replication occurs. As part of the virus life cycle, the cell is lysed and adjacent tumour cells infected thus perpetuating the anti-tumour effect. One major drawback was that TK deleted mutants were no longer susceptible to standard anti-herpetic agents like acyclovir, so the search continued to find newer and safer OVs.

Since the original work into TK mutants, numerous mutations have been engineered into OVs. The two most common genes to be inactivated or deleted are UL39 and γ34.5. The UL39 gene codes for infected cell protein (ICP) 6, which is the large subunit of ribonucleotide reductase and required in viral DNA synthesis. The γ34.5 gene product ICP 34.5 is involved in blocking host protein synthesis shut off mechanisms and neurovirulence. An article focusing on γ34.5 mutations is currenly in the pipeline. These mutations were engineered into the OV G207, the OV used for preliminary safety testing and phase I clinical trials in humans.

G207 possesses an inactivating insertional mutation of the E. coli lacZ gene into UL39. This locus is located in the unique long segment of the virus. The HSV contains two copies of the γ34.5 gene located in the two inverted repeat sequences flanking the unique long segment. G207 has deletional mutations in both those areas. In fact G207 is named as such because 34.5 multiplied by 6 = 207. G207 has demonstarted preclinical efficacy in a multitude of cancer models. In 2000, the results of a phase I clinical trial on the safety of G207 for use in intracerebral innoculation, in patients with malignant glioma was published.

Coming soon!

Oncolytic HSV and γ34.5

G47Δ: Making a more effective oncolytic virus

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