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Genotyping Tool Shop Shuns PCR and DNA Denaturing in Hopes of Attracting Pharma

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Gene Check, a small pharmacogenomics-technology company in Colorado may soon develop a novel SNP-genotyping technology that bypasses PCR and does not require DNA denaturing, a company official told SNPtech Reporter this week

The company last week won a $1.7 million grant from the National Institutes of Standards and Technology to validate the platform, which the company said may cut the cost of SNP genotyping to below $.02 per call — and in the process threaten to steal away pharmaceutical and diagnostics customers from the more expensive sequencing-based genotyping platforms.

“DNA analysis could be accomplished in hours, and affordable genetic profiling of patients could reduce hospitalization costs from adverse drug reactions by $1 billion to $4 billion” annually, Gene Check said in a statement announcing the NIST grant.

But these ends comprise the linchpin of pharmacogenomics, and are habitually touted as selling points by tool vendors and genotyping-service providers. Does Gene Check’s technology — which the company has only recently begun developing — have an edge?

In creating the platform, Gene Check decided to use a technology for homology searching in duplex DNA that didn’t require denaturing. The platform, which relies on off-the-shelf flow cytometry, uses oligonucleotide ligation to perform the actual genotyping.

“If we can get our oligonucleotides into the genomic DNA without denaturing it, we can be highly specific … and we can have huge cost-cutting advantages,” said Robert Wagner, president and CEO of Gene Check. The reliance on PCR and the need for target DNA denaturing “limits the multiplexing ability of almost every technique for SNP detection that’s out there.”

Wagner said the technology, which hasn’t yet been named, can be applied to research in which “huge” SNP panels are employed on a single DNA sample, such as “any kind of gene mapping.”

In principle, the technology could enable researchers to genotype more than 20 SNPs per second at a cost of less than $.02 per call, said Wagner. He said drug makers would be the technology’s first customers, and added that large reference labs would be “the logical second-tier customer.”

Gene Check would consider enlisting the help of developmental partners, especially large tool providers with diverse product lines, Wagner added. For example, he said, a company like Agilent with a strong investment in microarray technologies — which can be used to read Gene Check’s genotyping results — and that also has a controlling interest in a large array of SNPs “would be a perfect” partner. He added that a company with a “major interest” in flow cytometry, like Beckman Coulter or Becton Dickinson, would also be a welcome partners.

Wagner said the technology can service three pharmacogenomics applications: disease diagnostics, susceptibility testing, and targeted therapeutics. Wagner said the technology is being developed for these three applications in parallel, but added: “Let’s be realistic. … Personalized medicine depends on developments in terms of finding SNPs that can be used in the panels. So we’re not there yet.”

The technology might also be used in smaller diagnostics applications. For example, said Wagner, “Let’s say that the developments that seem to link P53 mutations to specific therapies continue to develop.” In this case, “we can make a panel designed to detect the most common 100 or 200 P53 mutations.” Gene mapping is another application in which the technology might fit “because the cost-saving advantages of being able to highly multiplex are enormous in that area.” Wagner stressed that Gene Check will likely partner with a diagnostics company rather than market a product itself. “We need to partner with someone who has rights and access to the SNPs of relevance to diagnostics,” he said. Like most other small technology companies, Gene Check doesn’t have the resources to hunt genes itself.

With 14 employees in its Fort Collins headquarters, Gene Check is privately held by a “very small number” of private investors, Wagner said. Beside the 3-year NIST grant, the firm has secured $300,000 through three SBIR grants. Wagner said Gene Check has not relied on private-equity funding, though that is not out of the question, he said.

Market Maneuvering

Some insiders speculate that if Gene Check manages to commercialize its platform, it will enter a market that is hungry for inexpensive tools that don’t skimp on multiplexing. To many, cutting costs means removing PCR. Vendors “need to provide [customers] with something simpler and cheaper,” said Jorge Leon, who heads a molecular diagnostics consulting firm, Leomics, in Princeton, NJ. “That’s a valuable position.”

Steve Johnston, founder and CEO of likely Gene Check rival Genetic Diagnostics, a Toronto-based startup that hopes to nudge PCR off its pedestal, agreed: “PCR is a clunky technology. But it was revolutionary. It opened doors, and it had a good run.” Johnston, who spoke with SNPtech Reporter in February about genotyping technologies that do not rely on PCR, said his company’s technology can run assays 80 percent faster than PCR [see 2/28/03 SNPtech Reporter]. Other potential Gene Check competitors are Naxcor and Third Wave.

Though he was unfamiliar with Naxcor’s or Genetic Diagnostics’ technologies, Wagner said Third Wave’s Invader platform has an advantage because it has been on the market for so long. However, Invader, which is a small-panel technology, “is very limiting in multiplexing abilities,” said Wagner. “When the market is for a lot of SNPs detected all at once from a single sample,” Gene Check’s technology will likely become superior, he said.

Oligonucleotide ligation-based SNP genotyping, meantime, is already considered an effective and affordable platform both by drug makers and academic researchers. A study in the February 2000 issue of Cytometry by GlaxoWellcome researchers found that “multiplexed SNP genotyping by [oligonucleotide ligation assay] with flow cytometric analysis of fluorescent microspheres is an accurate and rapid method for the analysis of SNPs.”

Two years later, writing in the Journal of Clinical Microbiology, a team of scientists from the University of Washington called OLA technology “rapid, simple, economical, and highly sensitive.” This team, led by Lisa Frenkel, of the department of pediatrics and laboratory medicine, used the technology to detect mutations linked to drug resistance in patients with HIV Type 1.

Ingrid Beck, a co-author of the latter paper, told SNPtech Reporter her lab developed its own oligonucleotide ligation assay largely because of its price compared to genotyping by sequencing. She said the lab intended to develop a technology that could be used by countries that are unable to afford expensive gene sequencing. She stressed that the technology “won’t give you the same information as sequencing,” but that it would enable people to test for mutations that confer high resistance to certain drugs. She said “it gets more expensive” if researchers wish to analyze each of the mutations for which it has developed oligonucleotides.

However, the absence of PCR would be a liability for Beck’s research. “The problem with HIV is that only a few extracted cells are infected,” she said, explaining that her lab performs nested PCR to obtain enough product to sequence the virus. She said the technology could be very useful for other kinds of drug discovery that study mutations in cellular genes.

— KL

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