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On the Other Side of The World, CSIRO Uses RNAi For Terrestrial, Aquatic Animal Applications

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BOSTON — Australia’s Commonwealth Scientific and Industrial Research Organization has been a pioneer in the development of RNA interference since the mid-1990s, working with plants such as barley, wheat, and potatoes.

But while CSIRO’s beginnings in the field started with and continues in plants, the organization believes its gene-silencing technology has potential in two of its other core areas of interest: livestock and aquaculture.

It was at CSIRO that a version of expressed RNAi, termed DNA-directed RNAi, was developed. The technology involves knocking down gene expression using DNA that transcribes double-stranded RNA, one strand of which has a sequence complementary to that of the target gene.

After securing the exclusive rights to the technology for all applications in animals (other than humans), plants, and insects following a protracted dispute with Benitec (see RNAi News, 12/12/2003), CSIRO is working on turning it into a way to combat diseases that threaten farm-raised cattle, poultry, and prawns.

According to Matt Lohmeyer, manager of RNAi opportunities at CSIRO, the market for antiviral treatments in livestock and aquaculture rivals, and in some cases exceeds, the market for many human therapeutics, as evidenced by the economic impact of recent disease outbreaks, particularly foot-and-mouth disease.

“In the UK [in 2001], [because of] foot-and-mouth disease 10 million [healthy and diseased] animals had to be put down,” Lohmeyer said, speaking this week at the Nucleic Acid World Summit in Boston. “The total damage to the UK economy, determined by the treasury [department], was in the order of $12 billion.”

FMD is a highly contagious small-RNA virus that belongs to the Picornaviridae family, Lohmeyer said. “It affects pretty much any cloven-hoofed mammal,” he explained during his presentation. Seven different serotypes of the virus have been isolated around the world, and each of them has a large number of subtypes that have evolved within it, he said. “That alone poses quite a challenge in order to develop … targeted therapeutics against this particular virus.”

But CSIRO sees RNAi as key to meeting this challenge. Already, the organization has been able to achieve roughly 80 percent survival in mice that have been injected with 100 micrograms of short-hairpin RNA expressing vectors and are then challenged by FMD virus, Lohmeyer said during his presentation. “That is quite a stunning result,” he added.

But achieving FMD protection in mice is a far cry from doing so in cattle, he conceded. Plainly put, “mice are not cows. While they are a surrogate host, they are a poor surrogate host,” he said.

“Size matters and it matters particularly if you are developing therapeutics for cows,” Lohmeyer said. “You give 100 micrograms per your average 20 gram mouse; what the farmer, using similar technology, would have to administer to his cow [would be] the mother of all plasmid preps.”

As such, CSIRO is working on a number of different delivery approaches for RNAi, including plasmids, tris-lipidation, and viral vectors. “In livestock, we can [also] work in areas like transgenics, and … explore the delivery of RNAi in something like bacteria or plants or algae,” Lohmeyer said.

To further advance its FMD work, CSIRO is also putting together an alliance of research institutions in the UK, US, Canada, and Kenya “to develop new and improved technologies to control the spread of foot-and-mouth,” including antiviral agents, Lohmeyer said.

“CSIRO is leading the charge to try and bring together these organizations,” he told RNAi News on the sidelines of the NAWS conference. Among the groups expected to contribute to the effort are the Plum Island Animal Disease Center; Canada’s National Centre for Foreign Animal Disease; the International Livestock Research Institute in Nairobi; the US Department of Agriculture Research Service; and the UK-based Institute for Animal Health.

Poultry and Prawns

Lohmeyer noted during his presentation that a US outbreak of exotic Newcastle disease in poultry last year caused damages of “a mere $175 million — very unfortunate if it happens to be on your farm.”

In addition, there have been recent outbreaks of avian influenza in Hong Kong, Mexico, Italy, Vietnam, and China, which threaten both humans and the $150 billion global poultry market. AI “is a very serious animal disease, but also has human disease implications,” Lohmeyer said.

“Our engagement in poultry is multifold,” he said. “We have active research programs to develop therapeutic approaches to treat the disease once it’s confirmed; preventative strategies like vaccination; and potential transgenic solutions that will hopefully avoid the problem occurring in the first place.”

As for aquaculture, Lohmeyer said that it is one of the fastest growing industries “spurred on by the fact that we’ve pretty much fished out the sea. In 2002, the industry landed about $54 billion worth of produce, [and] about $11 billion was due to crustaceans.” Aquaculture, he added, provides about 15 percent of the world’s total aquatic and terrestrial meat production.

“CSIRO’s engagement here is in a number of areas,” Lohmeyer said. “We’re looking at containment strategies, what we call sterile-feral technology … using gene silencing to prevent escapees from your aquaculture pens … from interbreeding with wild [animals].”

CSIRO is also exploring the use of RNAi in gender manipulation and in growth enhancement. Most importantly, Lohmeyer said, CSIRO is exploring the use of RNAi to achieve viral protection in prawns, which are susceptible to more than 10 major viruses including white spot syndrome and yellow head disease.

“In China, yellow head virus in 1988 stopped the growth of the Chinese industry dead, and [a] white spot virus [outbreak] a few years later pretty much wiped it out, causing direct losses of $1 billion,” he said. “That is on the order of [age-related macular degeneration] in terms of the kind of opportunity.”

CSIRO, Lohmeyer said, is currently engaged in establishing that RNAi works in prawns, and its researchers have just identified “the Dicer molecule in one of the standard prawns. The Dicer sequence is pretty much like the sequence we’re used to in humans, mammals, and plants.

“All the conserved domains are there, so the presence of Dicer suggests that RNAi also works in prawns,” he said. “Having validated the functional RNAi pathway, we’re now looking to target these multiple viruses and their variants.”

As CSIRO is forging ahead with these initiatives, it realizes that more can be achieved when research institutes partner with industry, and the organization is always on the lookout of commercial collaborators, Lohmeyer told RNAi News.

Already, CSIRO has partnered with undisclosed commercial entities for both its sterile-feral program and a gender manipulation-based pest-control project, and it is in discussions to strike deals on its other efforts.

“We’re looking to partner all of our programs,” Lohmeyer said after his presentation. “To bring industry on board early [is] really what CSIRO does in the sense that … our focus is to work with industry to develop new products and technologies.

“Some of [our work] will proceed without [a partner],” he added. “But our preference would always be to partner with an industrial collaborator who themselves can bring expertise and knowledge … so that we can make the best product.”

— DM

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