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Cancer Drug Shop BioVex Markets Legacy Technology for shRNA Delivery

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By Doug Macron

Looking to eke out value from technology developed before a corporate restructuring, cancer drug developer BioVex has been marketing vectors, originally designed for drug delivery, for RNAi-based target validation applications.

The technology comprises replication-defective herpes simplex viruses that express shRNAs and can be delivered to the nervous system both in vitro and in vivo.

BioVex was established about 10 years ago as NeuroVex to develop these viruses as vectors for gene therapies for conditions including Parkinson's disease and chronic pain, BioVex Founder and Chief Technology Office Rob Coffin told RNAi News this week.

"A couple of years in, we decided that was all a little bit too hard and changed track to try to treat cancer," he said. The goal here was to take advantage of the HSV vectors' ability to selectively replicate inside tumor cells and destroy them, while expressing immunostimulatory cytokines. Biovex's lead drug candidate based on this approach is currently in phase III testing.

Even though the company changed its focus and name, it still had the NeuroVex legacy technology, and began offering to manufacture vectors with custom payloads for academic and industrial partners on a fee-for-service basis.

"So over the last few years, we've had a separate [unit], still called NeuroVex, which basically constructs vectors with particular [customers'] sequences of interest in them to allow delivery of those genes to target organs for neurobiological research," Coffin said.

And at the request of potential clients, the company also began inserting RNAi sequences for gene knockdown.

In 2008, the company, in collaboration with Johnson & Johnson, published data demonstrating the ability of its vectors to deliver shRNAs to neuronal and non-neuronal cells in culture, and in the dorsal root ganglia in a transgenic mouse model.

HSV "is a naturally neurotrophic double-stranded DNA virus able to establish life-long latency in neurons," according to the paper, which appeared in Nucleic Acids Research. "Unlike other viruses that infect neurons, HSV has evolved to be efficiently transported from the nerve terminals innervating the infection site to cell bodies in vivo."

Having already shown that a replication-deficient version of the virus could transduce neurons and other cells efficiently and without toxicity, "we evaluated the potential of these vectors to deliver RNAi to peripheral neurons using a number of approaches," the study's authors wrote.

In the paper, they demonstrated that shRNAs could be expressed from the vectors using either pol II or pol III promoters, resulting in the "highly effective silencing of reporter genes in primary neuronal cells and DRG neurons in vivo." They also showed the system could be used to knock down expression of an endogenous gene, transient receptor potential vanilloid subtype 1, in sensory neurons of mice.

"These results highlight the potential of this technology, which can theoretically be directed to target any gene, as a valuable tool for the study of nociceptive processes and the development of new analgesic drugs," they wrote. "Furthermore, these vectors could ultimately be applicable to the development of an HSV vector-based approach to pain control."

According to Coffin, BioVex has already supplied shRNA-expression vectors to undisclosed pharmaceutical companies for use in target-validation studies. The company, however, is not planning to further develop the technology for such applications.

"There isn't any further work going on to make [the RNAi-delivery technology] better than it is," he said. "We've basically come to the conclusion that, in relatively simple terms, it was pretty easy just to insert the sequences into the vector and it appeared to work. As a result, if people send us sequences, which they wish to use for knockdown purposes, we can insert them … and send the virus back."

Coffin also said that the NeuroVex unit would be open to pursuing collaborations investigating therapeutic applications of the technology, but cautioned that he doesn't expect it to have too much potential in this area.

"If a company … felt that something we had made for them was sufficiently promising to not only be a useful tool for neurobiology, but also … potentially a therapeutic, then we would wish to work with them to make that a reality," he said. "But we don't have … expectations that [this] is to be the case. My personal view is that it's a far more useful tool for doing basic research than … for therapeutic use."

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