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Year of the rat

Andrew S. Wiecek

Sigma-Aldrich's SAGE Labs division and the Michael J. Fox Foundation are using zinc finger nuclease technology to develop knockout rat models for Parkinson's disease researchers.

Sigma-Aldrich will use zinc finger nuclease (ZFN) technology to create knockout rat models for Parkinson’s disease research. The development, which is funded by a research grant from the Michael J. Fox Foundation (MJFF), promises to create more accurate preclinical models of the disease.

After a proof-of-principle paper appeared in July in the journal Science using the ZFN technology to generate knockout rats via embryo microinjection, Sigma-Aldrich approached MJFF about using their ComproZr ZFN technology to develop new Parkinson’s disease models .

"We need better models [of the disease]," says Kirsten Carlson, associate director of research programs at MJFF. "[Sigma-Aldrich's] approach was highly novel, and a little bit risky." Despite the risk, according to Carlson the MJFF funded the project due to the potential reward such rat models could provide in advancing Parkinson's disease research.

Initially, Sigma-Aldrich's Sigma Advanced Genetic Engineering (SAGE) Labs division will use ZFN technology to design five knockout rat models, each targeting one of the five genes with known associations to Parkinson's disease.

A rodent is a rodent. Or is it?

While rats have been used in both basic and applied research studies for many years now, according to Phil Simmons, global marketing and business development manager at SAGE Labs, the mouse is currently king. "Researchers have a natural bias for mice. But, looking back, what we found was that before the mouse took over, the rat was actually the primary model." By searching research databases such as PubMed, researchers at SAGE Labs discovered that twice as many researcher accounts are using the word "rats" than "mice."

Simmons and his colleagues at Sigma-Aldrich believe this is because rats can make better model organisms in some cases when it comes to human disease, owing to the fact that rats are more physiologically similar to humans than mice for many traits. Because of this similarity, the hope is that they could make better models for research into neurological disorders such as Parkinson's disease than the current mouse models.

"There are knockout mice currently developed for these five genes [associated with Parkinson's disease]," said David Smoller, president of research biotech business unit at Sigma-Aldrich. "But the mice don't show the phenotype very well."

No existing model accurately mimics the onset and progression of Parkinson's disease in humans, according to Sigma-Aldrich and MJFF. But Carlson says researchers might have a better shot with new rat models. "Symptomatically, the rat shows a better phenotype, mimicking Parkinson's disease a little better."

And rats also have other advantages over mice since their larger size makes harvesting tissues and fluids, imaging, and behavioral assays easier when compared to mouse models.

The impossible rat

Before the emergence of ZFN technology, there had not been a viable technique for creating knockout rat models. While previous mouse models were created by cloning or using embryonic stem cells, ZFN technology promises to bypass these techniques by targeting genes in vivo creating knock out or genetically modified animals in a shorter amount of time and enabling knockout in a wider range of mammalian species.

As simple as ordering a reagent

SAGE Labs expects the the rat models of Parkinson’s disease will take about one year to develop. Once fully characterized, Sigma-Aldrich will make the rats broadly available to scientists throughout the Parkinson’s research community. "The plan is to sell rats on a per animal basis. When they are fully characterized, Parkinson's disease researchers will be able to purchase them as easily as they purchase reagents from Sigma-Aldrich," said Smoller.

Sigma-Aldrich has built a 25,000 square foot vivarium at its St. Louis facilities to house the new knockout animal models it will develop with ZFN technology as it plans to develop other knockout rat models for researchers in areas including cardiovascular disease, immunology, and toxicology in addition to neurological disease.