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Two Years After ExonHit Debuted SpliceArray, Firm Says Tool Will Replace Expression Chips

ExonHit Therapeutics last week capped two years of splice array product development by launching its Human Genome-Wide SpliceArray, which the company said offers users more than 23,000 human genes covering 130,000 expressed transcripts on a single microarray manufactured by Affymetrix.
The launch came nearly two years to the day after ExonHit initiated its SpliceArray service, which offers access to splice content for G-protein coupled receptors and ion-channel gene groups on its Agilent-manufactured microarrays (see BAN 2/9/2005).
In the two years since it launched the service, ExonHit has expanded its offerings to include arrays for other gene groups, as well as catalog arrays manufactured by Affymetrix and Agilent.
Now, with a genome-wide product on the market, ExonHit said last week that it believes that splice array technology could one day eclipse conventional expression arrays in the marketplace, a belief shared by others in the splice array field.
“We strongly believe that you will not be able to run global expression arrays without taking into account alternative splicing,” Laurent Bracco, ExonHit’s vice president of research, told BioArray News last week. “Any company whose official business is to sell arrays for expression must take splicing into account.”
Bracco’s views were echoed last week by rival Jivan Biologics, the only other firm in the market that specializes in splice arrays. According to Jonathan Bingham, chief technology officer at Jivan, the splice array market is poised for strong growth in coming years.
“Gene-expression arrays are designed to measure transcriptional activity, meaning pre-mRNA. But splicing is what turns a pre-mRNA, with all of its intronic regions, into a sequence that encodes a real functional product,” Bingham wrote in an e-mail to BioArray News.
“And we know that depending on the cell, the intracellular location, the disease, the drug treatment, and the patient, it may turn the same gene into different products with different functions,” he wrote. “Gene arrays miss all of this. Splice arrays get it.”
Held Back by Data Analysis
But if splice arrays will eventually outsell traditional expression arrays, as some claim, then why after two years is the market dominated by just three players — ExonHit, Jivan, and Affymetrix, which markets its exon arrays as a platform for alternative splicing studies?
According to John Jaskowiak, executive vice president of business and marketing at ExonHit, it will take time for researchers, particularly in pharma R&D, to embrace splice array technology.
“Pharmas and biotechs have begun to warm up to this area as they begin to understand that alternative splicing is at the root of elucidating the diversity of the human proteome,” Jaskowiak told BioArray News last week.
“I think it is only a matter of time that this will replace gene expression. It is gene expression at a higher resolution,” he said. “There are other activities, like software development, that could certainly help make it more seamless over time.”
Bingham similarly said that data-analysis needs were holding back adoption of the technology. To deal with that issue, Bingham said that Jivan spent most of 2006 developing SpliceFold, a splice array-specific data-analysis tool for use with its platform. The company launched the tool last month (see BAN 1/16/2007).
A major limiting factor so far has been data analysis, and this has slowed adoption of the technology and also kept more competitors from jumping in,” Bingham wrote. “Gene-expression software simply wasn't designed with the idea that there are multiple splice isoforms for the majority, around 75 percent, of human genes,” he added.

”We believe that the market is poised for big growth once customers are convinced that the data-analysis challenges have been addressed, and that they can readily take their results into the lab,” Bingham wrote. “When we talk to scientists in pharma and in academia, we are hearing that once this happens, splice arrays will largely replace gene arrays.”

Juan Valcárcel, a molecular biologist at the Center for Genomic Regulation in Barcelona, Spain, agreed that although the information provided by splice arrays could prove invaluable to scientists in coming years, the field right now needs to work through data-analysis issues to attract more users.
“If you are offered the ability to have this information as well, I don’t see how anyone would refuse that,” he told BioArray News this week. “The only thing I think that is preventing people from using this technology at the moment is how to analyze the massive amount of data,” Valcárcel said. “People are thinking, ‘If this is going to complicate my analysis, why should I use it?’”
Valcárcel’s lab currently uses three different platforms in its alternative splicing research: ExonHit’s platform, Affymetrix’s exon arrays, and an in-house-designed array manufactured by Agilent. He said that so far there is no “clear winner” among the rival platforms, and that each has its own strength.

“Any company whose official business is to sell arrays for expression must take splicing into account.”

“Affymetrix has a high capacity. The density of the probes that you can have on an array is really the best the market can provide,” Valcárcel said. “But the probes they design are of a short nature. Their designs also use mostly exon probes, instead of splice junction probes.”
On the other hand, the Agilent platform is “more flexible in terms of design, but the problem is that the density is much lower, so the coverage you can have is much more limited,” Valcárcel noted.
“I think the technology is still evolving,” he said. “I don’t think there is an optimal platform yet. Unfortunately, I don’t think there is a clear winner.”
Other users agreed. Ben Blencowe, a professor at the University of Toronto, told BioArray News in an e-mail this week that there is “considerable room for improvement in data-analysis methods.”
Blencowe currently uses arrays designed in-house and manufactured by Agilent for his alternative splicing research.
“Many current approaches look for ratio changes between probes for monitoring splice variants. However, various sources of noise can complicate such measurements and these need to be taken into account such that measurements can be appropriately weighted,” he wrote. “We're some way off from being able to optimally model the various parameters that can contribute to signal in microarray data.”
“To me, data quality is the number one key factor,” said Wenhong Fan, a scientist at the Fred Hutchinson Cancer Research Center in Seattle told BioArray News in an e-mail last week. Fan currently uses Affymetrix exon arrays to study alternative splicing.
“Better software helps in the downstream data-manipulation and statistical inference,” he wrote. “Academia has been the driving force to generate better quality data, given the current state of what technology can offer. However, there are limited statistics that one can do if data that comes from the hardware is problematic.”
New Products in the Pipeline
Despite the data-analysis challenges, companies that play in the market say that they will continue to release new products in coming months.
According to Jivan’s Bingham, the availability of higher-density arrays will enable the company to reach researchers that are interested in genome-wide studies. Jivan partnered with NimbleGen Systems in February 2006, and NimbleGen recently told BioArray News that it is planning to increase its density to 2.2 million probes per array this quarter (see BAN 1/2/2007).
“We see big opportunities in genome-wide splicing analysis thanks to the availability of higher-density arrays — 2 million features will be available soon — combined with our new software package that makes it much easier to filter and interpret the data,” Bingham wrote.  

ExonHit’s Bracco said that customers should eventually expect chips for new species, and that he expects the market to continue to grow.
“I think a natural evolution would be to add other species. We have worked on the human genome, but obviously adding the mouse and rat genomes would be very valuable,” Bracco said. “Definitely this is not a niche market. They are expression arrays and they are the new generation of expression arrays.”

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