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Dharmacon to Tackle siRNA Specificity, Efficacy Issues Through Rosetta Partnership

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Dharmacon said this week that it has formed a collaboration with Merck’s Rosetta Inpharmatics unit to assess the different factors that impact the efficacy and specificity of siRNAs.

The partnership comes about four months after researchers from Rosetta published a paper in Nature Biotechnology (June 2003, 21: 6, 635-637) demonstrating that chemically synthesized siRNAs, provided by Dharmacon, caused off-target silencing effects in two separate experiments.

The biggest culprits behind off-target effects, Dharmacon co-chairman and CSO Stephen Scaringe told RNAi News, are siRNA concentration and homology to other sequences, and the sense strand acting in the cell as the antisense strand.

“To solve these off-target effects, we found that, at least preliminarily, [we need to] reduce concentration, introduce modifications into the sense strand to block the sense strand from having off-target effects, and then [have] better BLAST algorithms and a better understanding of where to strategically place mismatches in the antisense strand,” he said.

Scaringe said that, under the collaboration, Dharmacon would work with Rosetta to refine its siRNA selection algorithms. This is expected to lead to better siRNAs that could be used in lower concentrations, and therefore eliminate one of the causes of off-target effects.

Scaringe said that Rosetta will also help evaluate the sense strand modifications Dharmacon has come up with and help improve his company’s understanding of base pair mismatches.

“We’re going to build on their observations of mismatches, because they’ve done a lot of work with the antisense strand, seeing that sometimes you only need 11 to 15 bases of homology … to get the siRNA hitting other targets,” he said. “We’re going to … build on their knowledge of mismatches to further reduce off-target effects and increase specificity.”

Scaringe declined to provide specific details about the collaboration, but said that he expects the companies will have met all their goals within six months.

Under the collaboration, Dharmacon will have the right to commercialize discoveries into its siRNA products and services. According to Scaringe, Rosetta gets early access to Dharmacon’s technology.

Additional terms of the arrangement were not disclosed.

Rosetta could not be reached for comment at press time.

—DM

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