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Genospectra Inks Deal with Dharmacon; Eyes Broader Cell-Based Assay Strategy

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Genospectra last week signed a deal with RNAi firm Dharmacon to bundle QuantiGene, its cell-based gene expression profiling assays, with Dharmacon’s RNAi technology in a single product offering.

The deal is the latest in a series of collaborations and product launches by Genospectra, of Fremont, Calif., a former player in the microarray arena that has recently shifted its focus to providing cell-based and other types of assays based on two core technologies: branched DNA, which is the basis of the QuantiGene product, and PAC (photoactivated cellular) probes, which will be available in a product offering later this year.

The technologies are part of a wider systems biology initiative the company calls “parallel quantitative biology,” the broad aims of which are to enable “multiplex measurements of molecular events, such as intracellular pathway analysis, in a quantitative and scalable manner.”

According to Melanie Mahtani, Genospectra’s vice president of business development, the company was originally founded to commercialize a highly parallel liquid deposition system for microarray generation. But, she said, this technology has since been outlicensed to two partners, and Genospectra has shifted gears.

At the heart of its parallel quantitative biology initiative is QuantiGene, a product based on “branched DNA” technology that Genospectra licensed from Bayer last year for use in life sciences applications. Bayer continues to use the technology in its clinical diagnostic assays.

“We had plans to take the fiber-optic technology and to develop high-throughput, parallel, dynamic assays along with the technology that we had in-licensed from Bayer,” Mahtani said. “What we decided to do was to deploy that in a different way than in an array. We thought that arrays were more inflexible.”

Branched DNA is just as the name implies: a molecular probe that at one end has many branches of DNA and on the other end has an oligonucleotide probe molecule designed to bind a specific target. In the case of QuantiGene, that target is mRNA in fresh cell lysates, tissue samples, or archived paraffin-embedded tissues. The branched DNA can then be detected with a chemiluminescent probe, producing a highly amplified signal.

The advantage of this, according to Mahtani, is that relatively small quantities of RNA can be detected without performing any intermediate steps.

“We’re actually measuring the RNA that was present in the cell when it was alive,” Mahtani said. “We’re not amplifying it, we’re not reverse transcribing it — we’re not really manipulating it in any way. This lets you go straight from a cellular experiment to a question about the transcript levels without the intermediate steps.” According to Mahtani, this also lends great accuracy to the assay — “variation on the order of two to six or seven percent, with about five percent routinely,” she said.

The specific advantage of this to researchers using RNAi — and the impetus behind Dharmacon inking the deal with Genospectra — is that “researchers can transfect an siRNA molecule into a cell, and know very quickly whether the RNAi knocked down the gene, and without the artifact of amplifying,” Mahtani said.

William Marshall, executive vice president of research and operations at Dharmacon, said that the company struck the deal because it wants to give customers an entire system based on its RNAi technology, so “they get results in a very ordered way [that] are meaningful.

“And one of the things you clearly have to do if you’re going to use RNAi to conduct functional genomics outcomes,” he added, “is to absolutely know that you can correlate whatever functional output you’re attempting to see … with the fact that you’ve got effective gene knockdown.”

Marshall said Dharmacon has been using QuantiGene in its own research laboratories for quite some time, and has validated its effectiveness for monitoring gene knockdown, even with low levels of RNA.

Drug Discovery

According to Mahtani, although about half of Genospectra’s customers are in the RNAi field, QuantiGene is also being used in drug discovery for secondary screening, and particularly predictive toxicology. “Researchers are [examining] animal tissues from the kidney, liver, heart, etc., and they’re asking: ‘Is my compound causing certain genes [that] are predictive of a toxicological response in those organs to go up or down?’” she said. “And you also want to know that pretty quickly, and without having to do [a lot of] RNA preps.”

Thomas Burris, a research advisor at Eli Lilly, said his group uses QuantiGene in nuclear-receptor drug discovery efforts. He said the group still uses other gene expression tools — for example, quantitative reverse transcriptase PCR methods like Applied Biosystems’ TaqMan — but that it has been steadily shifting towards QuantiGene.

“If you’re trying to do dose responses, differentiate between different compounds, and make decisions about which ones are better for structure-activity relationship determinations, that makes TaqMan difficult,” Burris said. “There’s much more variability. You can tell if something is being turned on, but you can’t always tell what the potency exactly is.”

Burris said that the ability to run QuantiGene assays on cell lysates in well-plates makes it similar to a reporter assay, with multiple points and low variability. He said that the assays can be automated, which can’t be done with TaqMan.

“Other companies have technologies to do this, but many require that you let them develop the assays” Burris added, “and sometimes they want to charge you a fee. With QuantiGene, it’s simple enough that you can develop the assays in house.,” he said. “You can buy the assays in kits and run with it.”

In the fourth quarter of this year, Genospectra plans to unveil a multiplexed version of the QuantiGene assay, which according to Mahtani will be able to assay 20 to 30 genes simultaneously — a level of throughput that should be attractive to drug discovery companies and basic researchers alike.

“That will be spectacular,” Burris said, adding that “we’ve seen some data and it’s very impressive.”

Dharmacon’s Marshall agreed. “The multiplexed version is very attractive to us,” he said. “Even with the simplest version — bi-plexing — you can now monitor, in the same assay well, a control gene and a targeted gene.”

Mahtani said that Genospectra has about 1,000 probe sets, including probes for humans, flies, worms, zebrafish, mice and rats, with the most popular being human, mouse, and rat. The company plans to provide a whole human-genome set of probes to complement Dharmacon’s genome-wide collection of siRNAs. This probe set, she said, will be available in September.

Living Cells

As Genospectra moves further into its parallel quantitative biology strategy, a push into live-cell applications seems inevitable. Mahtani said the company will indeed be addressing this area with its other core technology, PAC probes.

The probes are proprietary to Genospectra, which has filed for patents on the technology, Mahtani said. The PAC probes, she said, are designed to be able to do kinetics in real time in live cells. This is enabled by probes with a UV light-activated component, so the probes remain inactive until “turned on.”

“You transfect sensors into cells, and then you have the ability to turn them on at will,” Mahtani said. “That’s important because it allows scientists to control the timing of a reaction relative to other cellular events.

“A lot of assays are binding assays that are done outside the cell,” she added. “What we want are assays that can be done in a cell, and can be turned on and measured when you want relative to [the timing of] compound treatments.”

Mahtani said the company’s first PAC probe product is also due to be released late this year. There may be some instrumentation, she said, but added that “Genospectra doesn’t really want to be considered an instrumentation company. We like to be seen as a reagents provider. But where necessary, we are building instrumentation.”

The company is currently in the process of closing a Series C financing round. Expected to be completed sometime in August, it had the initial goal of raising $12 million, but Mahtani said “I think we’re going to hit that, and it will be more like $15 million.” She said the money will be used for the product launches and development, and to increase the company’s sales and marketing reach.

—BB

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