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Looking to RNAi, Ag-bio Field Faces Hurdles Similar to Those in Drug Development

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Although it has not embraced RNAi to the same degree as drug developers, agricultural biotech firms are increasingly interested in harnessing the gene-silencing technology to improve the yields of crop plants and to enhance their resistance to pests and environmental stressors, according to one industry insider.

Yet because of its relative nascence, ag-bio RNAi faces a number of challenges to its widespread application in the space, the greatest of which being what had long stymied the technology's use in human therapeutics — delivery.

Undoubtedly, the pharmaceutical industry was quick to start exploring the use of RNAi within its research and development initiatives, beginning with Merck and its 2003 partnership with Alnylam Pharmaceuticals, followed by other companies including Roche, Novartis, and AstraZeneca.

The ag-bio industry, in contrast, "entered the field a little bit later," Sergey Ivashuta, RNA technology lead at Monsanto, told Gene Silencing News. Nonetheless, "in the last two or three years, there has been a spike in interest" in RNAi, as well as microRNAs.

Indeed, there has been a spate of deals between companies in the two areas in recent years. In late 2011, DuPont signed a deal with Rosetta Green to identify miRNAs associated with drought tolerance in corn and soybeans. A few months later, Bayer CropScience partnered up with Rosetta Green on cotton-associated miRNAs.

Monsanto, meanwhile, has been active on both the microRNA and RNAi fronts. For instance, in 2012 it picked up access to Alnylam's RNAi technology and intellectual property for nearly $30 million, and earlier this year it bought Rosetta Green outright. The company has also already brought an RNAi product to the US market in Vistive Gold, a strain of soybeans engineered with the technology to yield trans fat-free and reduced saturated fat oil.

Helping drive his industry's interest in RNAi and miRNAs, Ivashuta said, has been a growing body of research — from both industry and academia — pointing to the potential of the two technologies in agriculture.

Of particular note was a paper appearing in Nature Biotechnology earlier this year in which a team of Chinese researchers showed that overexpression of a single miRNA could boost rice yield by as much as 25 percent.

Specifically, higher levels of miR-397 in the plant enlarges grain size and promotes panicle branching, leading to an increase in overall grain yield, according to the paper. And because the miRNA is highly conserved across grain species, its manipulation may prove useful in crops other than rice.

"Basically, you just use a noncoding RNA to regulate endogenous gene expression and tune the desired trait," Ivashuta said. "I think this is really amazing."

Yet when it comes to applying RNAi for insect control — one of the ag-bio field's biggest areas of interest — significant scientific hurdles remain, most notably related to delivery.

One of Monsanto's most promising pipeline products is a strain of corn that produces dsRNA designed to silence a gene involved in intracellular trafficking in corn rootworms, one of the biggest pests for corn farmers.

Called corn rootworm III, the product expresses dsRNAs against the gene Snf7, along with proteins known to be toxic to insects. Importantly, corn rootworms are responsive to what is known as environmental RNAi, wherein dsRNA is ingested and can trigger the RNAi mechanism through the gut. Thus, when the worms feed on the product's roots, they take up the dsRNA and the toxic proteins, which confer lethality.

Among insects, however, environmental RNAi "is not that widespread," Ivashuta explained. "This is one of the challenges to the widespread use of this technology" for pest control.

It is believed that most insects have the core cellular machinery required for RNAi, he said. But in terms of environmental RNAi, it is likely the animals' physiology that determines why some are susceptible and others are not.

For example, coleopterans such as the potato beetle have a fairly neutral gut environment with low levels of nucleases, which allow dsRNAs to remain intact after ingestion and make the pest a good candidate for RNAi-based control strategies. In contrast, lepidopterans such as moths, have a relatively acidic gut in which dsRNA "is very unstable," Ivashuta noted.

In essence, this is an issue of delivery, and "I think we can learn a lot [from] the delivery problem in the RNAi therapeutics area" by considering the ways that industry has been overcoming this problem, he added.

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