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Galapagos Inks Deals for Gene Silencing Technology with Boehringer Ingelheim, Wyeth

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Galapagos Genomics has not been the biggest name in siRNA reagents. But it appears that the Belgian biotech firm has just made its way onto big pharma’s RNAi map: This week, the company announced that it has signed two separate deals for its SilenceSelect siRNA-based gene silencing technology with Boehringer Ingelheim and Wyeth.

Since its founding in 1999, Galapagos has been offering target discovery services, using its adenovirus vector technology to deliver cDNA corresponding to specific genes. But in 2001, shortly after Tom Tuschl published his landmark paper in Nature describing the use of siRNA to knock down gene expression in mammals, the company began looking at incorporating RNAi into its focus, Galapagos CEO Onno van de Stolpe told RNAi News.

That work led to the development of SilenceSelect, a technology that involves the delivery of adenoviruses that express hairpin RNAs that are processed into siRNAs in the cell. “We make an oligo with a loop in between the two complementary strands,” van de Stolpe said. “When this produces an sRNA in the cell, it folds back and you get double-stranded RNA with a loop. Then the Dicer machinery clips off the loop and you end up with an siRNA.”

Using the adenovirus as a delivery vehicle, van de Stolpe said, Galapagos can deliver siRNAs into cells that ordinary transfection reagents cannot penetrate — namely primary cells. “Most of the researchers work with cell lines [which] often have lost the majority of characteristics of the original cell that they originate from. So if you are looking at specific cell processes, this might not be the right cell to work with.” However, “if you take a primary cell from the human body, and use that directly in your assay, you are much closer to the in vivo situation.”

The adenovirus technology also produces an extended knockdown effect, said van de Stolpe. “Where [with] normal transfected siRNA, you lose the effect after five or eight hours. With our system, [the knockdown effect] is still there after five or 10 days.” Galapagos recently detailed the technology in an article published in Genome Research. (See Genome Research, October 2003; 13: 2325-2332.)

Van de Stolpe said the company validated the SilenceSelect technol- ogy late last year and signed an unannounced deal this January to provide a pharmaceutical partner with siRNA-expressing adenoviral vectors against a number of select genes — a collaboration that wrapped up last month.

So while the SilenceSelect deals with Boehringer Ingelheim and Wyeth aren’t firsts for Galapagos, they are important milestones for the company’s efforts to get exposure for its RNAi platform.

“For us, it’s important that we now sign on several pharma partners to show the power of the [Silence Select] platform,” van de Stolpe noted. “Of course, we are kind of competing with reagent companies like Dharmacon and Qiagen.”

Under the deal with Boehringer Ingelheim, Galapagos will provide the German drugmaker with adenoviruses containing siRNA-based gene knockdown sequences for the more than 4,000 “druggable” genes. These include, van de Stolpe said, “GPCRs, the kinases, nuclear hormone receptors — all the genes that pharma has experience with in getting a small molecule drug.”

Galapagos expects to deliver the adenoviral vectors to Boehringer Ingelheim, which will use them to run assays on druggable genes that play a role in viral replication, before the end of the year. In exchange, Galapagos will receive an upfront fee, and is eligible for additional option and license fees down the road. Additional terms were not disclosed.

Under the Wyeth deal, Galapagos will not only create SilenceSelect adenoviruses but also conduct assay work to discover and validate drug targets related to bone formation. Wyeth has the exclusive option to license the targets for use in the development of osteoporosis drugs.

Galapagos said it will receive an upfront fee and research funding from Wyeth, and stands to be paid certain licensing, development, and commercialization milestones that could be worth more than $40 million.

“Wyeth gets an option to look at those targets for certain period of time, and if they decide … not to license them, they will return back to Galapagos, including all the data [Wyeth] has generated on the targets,” van de Stolpe said.

Galapagos may sell those targets not licensed by Wyeth to other companies or use them in its own drug discovery efforts, he added, as Galapagos works on transforming itself from a target discovery company into a small molecule drug discovery company over the next 18 to 24 months.

Development of RNAi-based drugs, he noted, will be left up to “the Alnylams of this world.”

—DM

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