Dharmacon and Odyssey Thera are marrying their technologies to develop a system of measuring inhibition of cellular signaling pathways with siRNA, the companies announced earlier this week.
For this joint exploration, Lafayett, Colo.-based Dharmacon is designing a set of siRNA reagents, using its proprietary design algorithm, for Odyssey’s protein-fragment complementation assays, which are used to quantify and analyze signaling events in living human cells. The partners will use this combined technology to look at pathways involved in angiogenesis, apoptosis, inflammation, and other disease-related events.
The project aims not only at gaining a clearer understanding of how siRNA works to silence cellular activity, but also at developing combined kits for more broadly applicable assays — or even at coupling the technologies in specialized drug discovery collaborations with pharma and biotech, officials from both companies told RNAi News.
On one level, Dharmacon is using these studies to address the scientific questions recently raised in papers by groups at Rosetta, Abbott, and Stanford about off-target effects and transience of siRNA, said Bill Marshall, Dharmacon’s executive vice president of R&D. This project will enable the company to be “the first in the world to really understand the specificity/potency issues around siRNA in the context of a living cell,” he said.
The research team, which will be led by Marshall and John Westwick, Odyssey’s vice president of drug discovery, hopes to submit for publication a paper presenting the results of these studies, and to have results by the end of the year.
Meanwhile, Dharmacon will also be “negotiating downstream around potential products that Dharmacon can market that would link the two technologies,” Marshall said.
Odyssey would go to pharma partners — either with or without Dharmacon—but “with the idea that the initial studies were powered by Dharmacon technology coupled with PCA technologies,” said Marshall.
Odyssey, of San Ramon, Calif., first approached Dharmacon with its technology with the idea of combining the two technologies, because “it occurred to us at Odyssey that siRNA was an ideal way to block pathway activity at a specific and very targeted point in the pathway,” said Aaron Solomon, the company’s vice president of business development.
“We also are quite confident that PCA is the best way to measure pathway activity. So combining these two technologies, you have the means to block a pathway or knock down the pathway activity, and then you have the means to measure the downstream effects in living mammalian cells,” he said.
The PCA technology, which was invented by Odyssey co-founder Stephen Michnick, a biochemist at the University of Montreal, uses fluorescent reporter protein fragments that are fused to proteins of interest, which then form complexes when the proteins of interest interact with one another. The folding of the complex causes it to emit a signal, indicating that the protein-protein interaction is taking place.
So far, said Solomon, Odyssey has close to 100 different assays based on PCA, which it uses in house. Dharmacon is supplying the company with siRNAs for “hundreds” of genes, Marshall said.
Although Odyssey initiated the project, it fits into Dharmacon’s strategy of trying to edge out the competition by becoming “an application developer,” of siRNA rather than simply a provider — a strategy that Stephen Scaringe, CSO, discussed in August with RNAi News’ sister publication GenomeWeb News.
At the time, Scaringe likened the situation to the early days of Sanger sequencing, when a provider of DNA oligo primers could either focus exclusively on producing oligos or try to expand its business to advance sequencing technology. “That’s what we’re doing by analogy with siRNAs,” he said.
In recent months, Dharmacon has executed this strategy in deals with Abbott and Exelexis to provide the companies with libraries of siRNAs for drug target genes, which have also been designed to help it further develop its own library of siRNAs for sale to other customers. And a collaboration with Agilent to combine siRNAs with microarrays has aimed at developing a standard protocol for use of the technologies together and joint products that combine the technologies.
“This is really going to the next level,” said Marshall. While global expression profiling with microarrays “is a way that you can essentially take a fluorescence picture of the transcription state of the cell, in this technology you can get a picture of the protein-protein interaction states in the context of the living cell. So it’s the next level in complexity and it’s actually more relevant overall.”
The companies did not disclose the financial terms of the agreement.