Insect virus in cancer therapy

For the first time, a research team from the NUS Department of Biological Sciences and the Institute of Bioengineeing and Nanotechnology has demonstrated the effectiveness of a virus isolated from insects, in cancer therapy -- in an animal model. Findings of their research were published in a paper, Recombinant Baculovirus Containing the Diphtheria Toxin A Gene for Malignant Glioma Therapy carried in the journal, Cancer Research (June 2006).


Associate Professor Wang Shu who leads the project in NUS, explained that the insect virus (known as baculovirus) as a vector or vehicle to deliver therapeutic genetic materials into the body, has been known some 10 years ago. But its effectiveness in cancer therapy has not been demonstrated -- until now.

BACULOVIRUS: They belong to larger-sized virus family and are good vectors as they do not replicate in human cells. "Glioma" is a type of primary central nervous system tumour that arises from mutation of glial cells, with great tendency to invade aggressively into the brain. Grade 4 gliomas or gliobastoma multiforme is currently almost incurable. Even with surgical intervention, radiotherapy, and chemotherapy, patients with gliobastoma multiforme usually die within a year, with only a few patients surviving longer than three years. Gene therapy would be a promising form of treatment for such cancer -- using various types of viral vectors with gene expression regulation elements. Virus is a good vector because it penetrates easily into cells of our body.

Associate Professor Wang's research has shown in vitro and in vivo, that the baculovirus is an excellent vector for carrying therapeutic genes into the brain-- enabling the therapeutic genes to reach their targets to eliminate tumour cells. The research team used the baculovirus Autographa californica multiple nucleopolyhedrovirus in their experiments -- a virus traditionally used as biopesticides to kill infected insects.

His team found that with mammalian expression promoters (to regulate the expression of therapeutic genes once introduced into the body) recombinant baculoviruses provide high transduction efficiencies in many different types of cells and tissues, including several tumour cell lines.

"One of the greatest advantages of using baculovirus as a vector is that it does not replicate in human cells, unlike mammalian virus in the human body," said Associate Professor Wang. Another advantage is that the human body, commonly exposed to mammalian viruses, readily rejects them through its immune responses -- which is not the case for insect virus. And because of its bigger size, it can deliver a large functional gene or multiple genes into the human body to carry out their therapeutic work. Baculovirus belongs to the family of large-sized viruses. Its rod-shaped body measures about 200 to 300-nanometre long, with diameters of 20 to 38 nanometers.

The team's recombinant baculovirus vector carried the Diphtheria Toxin A Gene (DT-A) gene which has been tested in cancer therapy. This bacterial protein is highly toxic, inhibiting protein synthesis and hence, able to kills cancer cells. Once introduced into the body by the baculovirus vector, it would be triggered to work by a protein (the glial fibrillary acidic protein, GEAP) which is also engineered into the vector. Due to its high toxicity, the use of DT-A requires the use of a "promoter" to control its expression and to avoid killing of non-target cells.

"Although baculoviruses seem to be more prone to infect glial cells than neurons in the brain, we would still need the use of a glial cell-specific promoter to reduce potential side effects on neurons caused by over expression of the therapeutic gene, especially when a toxin gene like DT-A is used," explained Associate Professor Wang.

"Further development in the use of this insect virus vector would certainly open up new opportunities for virus-mediated gene therapy for other diseases," he added.

Offering an optimistic glimpse into the future, he said: "One day, we may be able to introduce viral vectors carrying new therapeutic genes, like siRNAs. These genes have been demonstrated to be effective in killing cancer cells in vitro."