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Divergence Sees Opportunity, and Money, in Using RNAi to Fight Parasitic Nematodes

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Can you make money from worms? Divergence, a small biotechnology company in St. Louis, thinks it can. The company is using genomics approaches — including RNA interference — to develop highly specific chemicals and drugs against parasitic nematodes.

The market for such improved nematicides could reach several billion dollars, according to Divergence president and CEO James McCarter. It would include nematicides to protect plants, transgenic plants that make their own worm toxins, and anti-nematode drugs for animals.

McCarter founded the company in 1998 while he was working on sequencing nematode genomes as a postdoc in Robert Waterston’s laboratory at the Genome Sequencing Center at Washington University School of Medicine.

The idea, he said, was to look for worm genes that have diverged from human genes — hence the company’s name — and focus on these as potential targets. This approach would ensure that any chemicals developed against them would be toxic to worms, and not to humans or other organisms.

After using computational genomics to find such potential targets, “what we needed is a functional genomics filter” in order to select those genes that play a crucial role in the worm physiology and make effective targets, said McCarter. “And that’s where we have used RNAi interference,” he said.

Divergence started using RNAi as early as 1999, and in 2000 performed a screen in which researchers knocked out about 1,200 parasite-specific genes in C. elegans. “We were able to generate much of this data 12 to 18 months in advance of the publicly available data,” McCarter said.

Only about 100 genes showed a strong phenotype in the screen, which “really helped us to focus our efforts down to a more manageable number of targets,” he added.

Divergence researchers whittled those down to fewer than 20 targets, and are developing chemicals against these targets, which consist mainly of enzymes with a known function, as well as secreted or transmembrane proteins on accessible surfaces, such as the worm’s intestine.

But Divergence is also now using RNAi technology, in next-stage R&D, with new C. elegans strains that have “unusual properties” such as tissue-specific RNA interference. “That’s allowed us to go back and generate new pipelines, generate information that’s not in the public domain,” McCarter said.

In addition, the company has been working on plants that produce double-stranded RNAs internally to kill parasitic nematodes

The main advantage of RNAi interference for finding suitable targets was its speed and throughput, compared to gene knockouts in worms, McCarter said. “We were able, with a very small group, to get up to knocking out 80 genes a week, with only partial effort,” he said.

However, RNAi screens miss out on targets for drugs that cause a gain of function, for example an opening of channels, he said.

Also, chemicals developed against a target defined by RNAi might show a different phenotype, because they block, for example, an enzyme rather than its messenger RNA.

Meanwhile, Divergence has been building up its chemistry group and greenhouse operations, primarily to focus on developing nematicides for agriculture. “It’s hard to name a crop that doesn’t have a problem with nematodes,” McCarter said.

So far, it has developed three groups of chemicals against enzymatic targets. Two of them are active on human, animal, and plant parasites, whereas one is specific to plant parasites.

The one that is furthest along in development is derived from a natural plant product. While it shows efficacy against plant parasitic nematodes, it “lacks toxicity to rats, to fish, to earthworms, [and] to insects,” McCarter said.

Right now, the company is working on optimizing the chemicals so they would be more effective, stable sufficiently long enough and be able to penetrate the plant.

But the path to commercialization could take up to seven years, McCarter said. With the possible exception of the natural plant product, the company would have to obtain approval from the Environmental Protection Agency, the equivalent for agricultural chemicals to a drug approval from the US Food and Drug Administration.

With regard to anti-nematode drugs for animals, Divergence has outsourced all animal testing to contractors.

Equipped with NIH funding, the company is also doing research into developing drugs for humans, in particular a macrofilaricide to treat African river blindness and elephantiasis.

Eventually, Divergence is planning to develop products in partnership with a larger company, and is currently in discussions with a number of companies in crop protection, transgenic plants, as well as animal health,said McCarter. “We largely see our work as what would traditionally be defined as discovery.”

—JK

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