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Running with ‘magic scissors’
October 2008
by Jeffrey Bouley  |  Email the author
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ST. LOUIS—Zinc finger nuclease (ZFN) technology isn't new, but Sigma-Aldrich believes it now has the platform, the reach and the strategy to get it out in the mainstream of genomics research. In mid-September, the company introduced its CompoZr ZFN platform, which will be available first as a customized service for developing ZFNs for specific gene targets. Moving forward, though, CompoZr will eventually include ZFN-based kits for targeted transgene insertion and a catalog of off-the-shelf reagents for commonly studied gene targets, gene families and pathways.
 
By bringing ZFN technology in house at Sigma-Alrdich, the company has slashed production times related to using ZFN methods, and this will make the technology far more accessible to the market, notes David Smoller the president of Sigma-Aldrich's research biotechnology unit. In fact, the company is banking on the utility of ZFNs to encourage "widespread adoption" of the CompoZr platform, even though ZFN technology has yet to lead to production of a blockbuster pharmaceutical.

Over the past decade or so, ZFN technology has at times been described as "magic scissors" for genomics. As Sigma-Aldrich describes the technology, ZFN reagents are a class of engineered DNA-binding proteins that facilitate targeted editing of the genome within a living cell by creating double-strand breaks in DNA at user-specified locations.  Double-strand breaks stimulate the cell's natural DNA-repair processes, namely homologous recombination and non-homologous end joining, to induce site-specific mutagenesis.

This means researchers using CompoZr reagents will, for the first time, be able to generate precisely targeted genomic edits in rapid, single-step procedure, giving them cell lines with permanent and heritable gene deletions, insertions or modifications, Smoller says.

"This is going to herald a new stage in genetic engineering and insight into gene function. To my mind, it's a Holy Grail," Smoller says. "Zinc Finger Nuclease technology has held significant promise for more than a decade and is now mature enough to fundamentally alter the way in which research on living cells and organisms is conducted. Something like RNAi is a great tool for knocking down a gene, but it's only transient, or turning down a gene, not getting rid of it. We offer pure knockout."

The downside of the technology is that it isn't a high-throughput process right now, though Sigma-Aldrich is working on that, and as its custom work continues and the company adds more ZFNs as off-the-shelf reagents, things should speed up.

"If someone wants to knock out 10,000 genes a week, they aren't going to get that, but we are working on technology that will allow for thousands in a year," Smoller says. "We make the gene from scratch over six to eight weeks, so it is all custom right now, but our goal is to have validated zinc fingers on the shelf for every gene, however long that takes, so that it will be more cost-efficient."

In addition to moving the platform in quicker and more off-the-shelf directions, the company also is collaborating with some leading academics to generate novel animal models of disease that more closely mimic human disease, using ZFNs. In fact, Sigma-Aldrich recently commenced a collaboration to create the first ever transgenic knockout rat using ZFN, and is working with other researchers to get work going on mice, rabbits and other whole-animal knockout models.

By facilitating the creation of complete gene knockout and knock-in somatic, embryonic and primary cell lines, ZFNs allow researchers to precisely determine the biological function of a gene in more relevant backgrounds, according to the company. Sigma-Aldrich anticipates ZFN-mediated genome editing could be used to generate novel animal models of disease to mimic, more closely, human disease, as well as providing more realistic data on the potential toxicity of new drug compounds. For biopharmaceutical manufacturers, ZFNs will enable the creation of cell lines with improved growth characteristics, altered glycosylation properties and other traits resulting in higher yields. DDN
 
Code: E100813

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