Although it is no longer pursuing the technology, Cambria Biosciences sees potential for an RNAi-based pest management method it developed a few years ago as a research tool, and is on the lookout for parties interested in out-licensing it, according to Scott Chouinard, director of molecular biology at Cambria.
Cambria was founded in 1998 as an agricultural and animal health firm, but changing market conditions led it to shift its focus to human therapeutics for central nervous system disorders. As part of that change, the company shelved a program exploring the use of RNAi as a pest management technology, Chouinard told RNAi News this week.
“Companies [in the agricultural and animal health space] keep merging and consolidating, so there are fewer companies to do business with. [As a result], it’s harder to find partners in these areas [and] funding is harder to get,” Chouinard told RNAi News this week. “We knew that wasn’t the case with the human” therapeutics field, so Cambria began refocusing on CNS drugs about two years ago.
Although Cambria’s change in direction is a major one, the company’s earlier work does not appear to have been wasted. “It might seem very unusual to go from one area to the other, but the reason is … that almost all of your very good insecticides, especially those that kill quickly, work on the nervous system,” Chouinard said. “A lot of [the] targets [of insecticides] — sodium channels, gamma receptors — are targets for therapeutics … so this jump to the central nervous system isn’t really all that illogical.”
The move to becoming a drug maker is not complete, however, and Cambria still conducts some insecticide work. But it is now strictly chemical-based, and work on an RNAi-based pest control product has been dormant for over a year.
The technology, which is protected by two patents, involves the use of an expression vector that produces within a particular pest a double-stranded RNA that inhibits an essential gene. “In a preferred embodiment of the invention, the expression vector is a recombinant baculovirus that transcribes sense and antisense RNA under the control of the baculovirus IE-1 promoter and hr5 enhancer,” the primary patent covering the technology — No. 6,326,193 — states.
“We were [initially only] interested in chemical [pest] controls, but as we were thinking about technology to bring into the company to help us understand gene function in non-genetic-tractable organisms like the insect pest, we started to think about how we could knock out genes, and it was clearly RNAi,” Chouinard said.
“While we were thinking about it, we were very aware of baculovirus, and we were thinking that maybe we could use [it] to deliver double-stranded RNA to the larval and adult insects to study gene function,” he said. “Then, we started thinking, ‘Why don’t we make this the insect control agent?’.”
Chouinard said that baculovirus itself is an insecticide, but works rather slowly and is limited in the kinds of insects it works against. To overcome these issues, the company’s researchers took “a natural baculovirus promoter, [which] would be recognized by the host insect machinery or by viral-transcription machinery and [made] a duplicate promoter,” he explained. The company’s researchers then generated a vector that had two convergent promoters, and a fragment of the gene of interest was inserted into a multiple cloning site between the two promoters. When activated, both promoters would synthesize their transcript and the two strands of RNA would anneal within the cell, he said.
Chouinard said that the RNAi program was put on the back burner after Cambria’s attempts to market the pest-control approach did not pan out. “What we found when we were going around talking to companies was that they hear that we were working on baculovirus, and they were trying to sell us their technology,” he said. “This would be a very expensive product to move forward and we were looking for bigger partners to take it over, but none of them were interested.”
Though Cambria claims its RNAi-based pest control approach offers certain benefits over other insecticides, such as specificity, the technology faces a handful of major issues that Chouinard conceded have hampered commercialization.
“None of the large agrichemical companies work on baculovirus anymore — they’ve all sold off their technology to universities or very small companies” since the limitations of wild-type baculovirus as a stand-alone insecticide essentially eliminate the market for it, he said. As such, finding a partner has been troublesome.
As far as developing the virus with Cambria’s RNAi approach, the company had hoped it could increase the number of pest types baculovirus would be effective against, “but that’s a very difficult biological hurdle to overcome [due to] the way baculovirus enters [different] insects,” Chouinard noted
The cost of manufacturing baculovirus is also fairly high, he added, and “when you throw on top of it that you’re introducing a genetically modified virus … getting it past environmental groups” would be a significant challenge.
But all might not be lost for Cambria’s sole RNAi program.
“One thing that we would like to see come from this is … not [using] this as an insect control agent for putting in the field, but for [use in] academic labs that are interested in doing some genetics in Lepidopteran,” Chouinard said.
For example, “some companies have sequenced heliothis, which is a big cotton pest, but you can’t do genetics on them — these things have a huge number of chromosomes, their genomes are very large,” he said. “But what would be useful would be to use this technology to do some reverse genetics in some of these insects. Now that the genomes are available, let’s go ahead and engineer double-stranded RNA constructs in baculovirus vectors and infect the organism to see what kinds of phenotypes we see.
“That’s where we think there would be the greatest utilization of” our technology, Chouinard said.
— DM