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In NuGen Deal, Affy Reveals New Plans To Develop Next-Generation GeneChip

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A new collaboration between Affymetrix and NuGen technologies in the area of RNA amplification technology has revealed that Affymetrix is planning to develop next-generation GeneChips—microarrays that interrogate the entire transcriptome, including splice variants, for the human genome.

This array would be the next step for the company after the single-chip, whole human genome array (U133 Plus 2.0) it debuted in October.

Under the deal, announced this week, NuGen said it will develop amplification reagents that replicate the whole length of mRNA transcripts, and the companies will work together to optimize the reagents for the next-generation GeneChip arrays. “Our collaborative efforts are focused on providing the most powerful product solutions to drive the entire field of whole genome analysis forward,” John Blume, Affymetrix vice president of expression research, stated.

Affymetrix began talking with NuGen about the deal, according to Lianne McLean, the company’s director of gene expression marketing, “because we are considering the development of arrays, in the next 12 months, that interrogate features at any position across a full mRNA transcript and that are not necessarily near the 3’ end on the molecule. As a result, we’re looking at multiple approaches for generating hybridization target without a 3’ bias.”

NuGen, a three-year old, 35-person venture-funded company located down the road from Affymetrix in San Carlos, Calif., is pleased as punch to be working with Affymetrix. “The value [of the collaboration] to us goes well beyond financial terms,” said Jan D’Alvise, the company’s CEO. “We view [the amplification reagents] as a very important product to NuGen, and I believe that Affymetrix views their next-generation arrays as being very important to their future growth as well.”

At its core, the collaboration addresses a problem that has long been whispered about in microarray circles and discussed in the fine print of scientific journals: alternative splicing.

With current GeneChip technology,“the length of the gene where the probes are selected from may be up to 1,000 bases: Most of them are actually quite a bit shorter than that,” said D’Alvise. “You get these alternative splicing events that take place downstream. And you miss those with today’s microarrays, and with the sample preparation technology on the market today.”

NuGen has adapted its Ribo-SPIA (single-primer isothermal amplification) technology so that it can amplify and label the entire transcript of genes, even if the genes are up to 20,000 bases long. “This is a new, very revolutionary technology that will enable full-length amplification,” D’Alvise said. “And what it means is that Affymetrix will be developing a chip that has probes that cover that entire length of the transcript as well.”

Andrew Brooks, the director of the Functional Genomics Center at the University of Rochester Medical Center and a member of the scientific advisory board at NuGen, said this collaboration is part of a new level of gene expression analysis, in which expression is understood “as a function of splicing and editing.” To “get a handle on these events, you need to understand the entire transcriptome,” he said.

The collaboration between Affymetrix and NuGen also has practical business value for Affymetrix, which no longer has a reagent labeling partner it can count on: In October, Enzo Life Sciences, which up until this summer had provided the standard labeling kits that Affymetrix sold with its GeneChips, filed a breach of contract suit against Affymetrix in the United States District Court for the Eastern District of New York (see BAN 11-12-03).

This deal does not replace the partnership that Affymetrix had with Enzo for current labeling protocols. But it does assure that Affymetrix will have a new partner in amplification and labeling reagents for future GeneChips.

For the current generation of chips, McLean said Affymetrix “is planning on launching a new, complete reagent product line” that will “provide customers with the optimal performance on these arrays.”

Additionally, NuGen announced in October that it was sending to early access partners the Ovation RNA amplification and biotin labeling system, a labeling kit for current-generation GeneChip microarrays.

With this biotin kit, users “start with total RNA and end up with labeled product to put on your Affymetrix GeneChip,” and therefore it “removes Enzo,” said Brooks, an early access partner.

D’Alvise firmly emphasized that NuGen is pursuing a strategy of direct sales for the biotin product and its other current product — an Ovation amplification and labeling kit for two-color arrays launched in July — and is not considering a distribution partner like Affymetrix. The presence of this kit on the market does, however, offer users of Affymetrix arrays a commercial option other than Enzo, even before the company launches its own reagents for current GeneChips.

But the core reason why Affymetrix chose NuGen as a partner may ultimately have much more to do with labs than lawsuits.

“We were attracted to the NuGen system by the potential increase in speed of target preparation, the overall ease-of-use of the NuGen system, and the early array performance results,” McLean said.

NuGen’s ovation reagents are indeed much faster and more sensitive than current T7 linear amplification technologies, according to Brooks. With the NuGen system, which requires only one round of amplification, “you are looking at cutting down a five-day process to about half a day,” he said. And because there are less manipulations of RNA involved, the reproducibility increases.

Brooks said that he is looking into automating the process in his lab because it is so straightforward. In fact, D’Alvise said, several of the company’s customers have automated their amplification on commercially available robots.

The SPIA technology was invented in 1999 by Nurith Kurn, the company’s co-founder and chief scientific officer. In June 2001, the company received a patent for the technology, No. 6,251,639, and has filed additional patents.

The company has also so far raised $20.3 million in venture financing, including a $7.5 million series C closed in August led by William Rutter, co-founder of Chiron; George Rathmann, founder of Amgen and former CEO of Hyseq; and James Wilson, former president of Syntex, Neurex, and LifeScan.

While the Affymetrix collaboration and the new product launches have the growing company busy for now, in the future, NuGen intends to apply the technology to other applications beyond RNA amplification for microarrays.

“Our mission right now is to really become the standard for sample preparation for gene expression,” said D’Alvise. But, she added, the company is already looking into other applications of its technology in DNA- and protein-related” areas. And, in the future, certainly we’re looking at the clinical diagnostic market,” she said. “We really believe this is a very powerful technology that really should find its way into the clinical sector in the very near future.”

— MMJ

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