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Knocking it out of the park in the human genome
ST. LOUIS—Sigma Life Science, the biological products and services research business of Sigma-Aldrich, recently announced the release of its predesigned CompoZr Knockout Zinc Finger Nucleases (ZFNs) technology that reportedly can generate permanent and heritable gene knockouts in human cell lines within weeks, touting the new offering as "attractively priced to fit within the budget of a typical laboratory."
Currently, few laboratories create gene knockouts in human cell lines because of the inefficiencies of the natural cellular homologous recombination system and the investment of time and labor required to screen the resulting cells, according to David Smoller, chief scientific officer of Sigma Life Science. "Sigma Life Science has worked diligently to develop predesigned CompoZr Knockout ZFNs for each gene in the human genome to make this groundbreaking technology more readily available to the research community," he says. "Researchers can select a ZFN from our library and swiftly knockout their target gene in any human cell line."
Sigma isn't a stranger to making news with the ZFN technology, having roughly a year ago unveiled what it said was the first suite of knockout rats for ADME/Tox applications. At the time, Dr. Edward Weinstein, director of Sigma Advanced Genetic Engineering (SAGE) Labs noted: "Until now, the availability of relevant, genetically modified rats was limited. Knockout mice are readily available, but very challenging to use in ADME/Tox applications due to their size and physiology. We've changed that. Our knockout rat models offer a platform that can potentially save millions of dollars in development costs for potential drug candidates by providing a more human-like model, and at the same time significantly decrease time to market for these therapeutics."
Now, bringing things even closer to humans, Sigma says it has designed CompoZr ZFNs that will produce a knockout in each human gene by inducing a double-strand break at a defined site within the gene's first three exons. This double strand break reportedly stimulates the cell's natural DNA repair pathways, resulting in a permanent, site-specific deletion or mutation that disrupts the gene's function. More sophisticated genetic modifications, such as single nucleotide substitutions, can be generated through Sigma Life Science's CompoZr Custom ZFN Service.
"This technology is pretty game-changing to begin with, even before the human gene offerings," Smoller tells ddn. "When Sangamo came out with ZFN technology, the cost was in the hundreds of thousands of dollars. When we got to it and got our product group around the technology, we were able to do a lot with the affordability and robustness of the technology and do a custom program charging $25,000 on average for a zinc finger. Since then, we've been able to go even farther to change single nucleotides, insert over 8kb of DNA into genomes, make cells glow, create the first schizophrenic rat and p53 oncology rat, and more."
While he says the human genome ZFNs represents a big milestone, the larger message is making the ZFN technology more generally accessible and affordable to researchers, Smoller says. To that end, some of the next steps for ZFNs are to expand into larger animals—such as rabbits and monkeys—that, like rats, have been very refractory to gene knockouts compared to mice. ZFNs, Smoller notes, could do a lot to reduce the number of animals that researchers have to go through in studies of drugs by allowing them to create better animal models to begin with.