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RNAi Roundup: Alnylam Expands Staff As it Speeds to Clinic; Dharmacon, Agilent Project Could Lead to Products; Scaringe Denies He s Left Dharmacon

NEW YORK, June 27 - Short interfering RNA therapeutics firm Alnylam will likely have products in the clinic within two to three years, CEO John Maraganore said in an interview at the BIO 2003 meeting in Washington, D.C. this week.


The Cambridge, Mass., company also plans to beef up its staff, from 30 employees at present to 45 by the end of the year, Maraganore told GenomeWeb's sister publication Genome Technology.


This short-term optimism comes from the company's belief in the underlying science.


"RNAi is probably the most important biological discovery in the last two decades," Maraganore said.


While a number of companies are planning to cash in on this discovery, Maraganore said the company's strong IP position in the field and the prowess of its scientific founders give it an edge.


Alnylam holds an exclusive license for therapeutic use of short interfering RNA from a pair of seminal patent applications held by MIT, the Whitehead Institute, the Max Planck Institute, and the University of Massachusetts Medical School. The firm was founded by the inventors on these patents Tom Tuschl, Phil Sharp, Paul Schimmel, David Bartel, and Phillip Zamore.


Maraganore, a former senior vice president of strategic product development at Millennium Therapeutics, came on board at the beginning of the year. 


His to-do list for the remainder of 2003 includes enough items to make even a super type-A executive sweat. They include: continuing to build the company's R&D team, demonstrating in vivo action of siRNA in animals; advancing the company's drug pipeline toward the clinic; and expanding the company's IP portfolio -- oh, and by the way, landing a partnership with a pharmaceutical company.


The problem of demonstrating in vivo action of siRNA in animals, alone, is daunting. In May, at a Waltham, Mass. conference on RNAi, Alnylam director of corporate development Nagesh Mahanthappa said the company has been able to achieve knock out of genes in mice using hydrodynamically delivered siRNA. But like other companies, Alnylam still has to figure out how to find a clinically feasible way to deliver siRNA that is both efficacious and non-toxic.


Earlier this week, siRNA provider Dharmacon announced it was teaming up with Agilent Technologies to evaluate the use of Agilent's microarrays with siRNA technology.


The researchers "are going to use the microarrays to confirm, first of all, that you are actually silencing the gene you are targeting," said Christina Maehr, an Agilent spokesperson. Secondly, she said, the arrays would be used to determine "the ramifications on the rest of the cell -- whether silencing one gene affects ten others or forty."


The group of researchers will also use the Rosetta Resolver software to analyze the effects of RNAi on gene expression. This is a research collaboration, so there are not significant financial terms involved as yet. The companies are more interested in "defining methodologies" for using microarrays with siRNA, Maehr said.

These proof-of principle experiments, if successful, are likely to lead to products that combine siRNA with expression profiling, according to Dharmacon executive vice president of R&D Bill Marshall.


Marshall said the collaboration came about after "discussions with various providers of microarray technology." The company chose Agilent, he added, due to their ability to provide "access to high-quality global expression chips, as well as their ability to rapidly generate custom chips."


The idea of linking siRNA and microarray technology also stemmed from the issues of off-target gene silencing activity that have lately been swirling around siRNA, according to Marshall. "If you are going to move forward on a pathway of more significant development of an siRNA, one wants to ensure that you do have some clear specificity issues under control, and the best way you can do that is to look at global expression profiles," Marshall said.


Additionally, combining the technologies may be useful in systems biology: when you know the other genes that are affected by an siRNA knockdown or knock-out, "you can help place this gene into a pathway," Marshall said.

Finally, he said, there is the idea that siRNA verified by gene expression experiments can serve as a "golden fingerprint" of gene inhibition that pharmaceutical researchers can use as a standard against which to measure small-molecule inhibition of various gene targets.


The wetlab work will take place in Dharmacon's Lafayette, Colo., facility, while Agilent will handle data analysis, Marshall said. 


Meanwhile in the management arena, Dharmacon founder and CEO Stephen Scaringe emphatically told GenomeWeb that rumors of his leaving the company were "not true." He said he had no further comment on the matter, but that he would hopefully be able to comment in the near future. Last week, Marshall told GenomeWeb that the company was "in negotiations" with Scaringe about his future role at the company.


In RNAi research, a report published June 19 in Nature demonstrating the use of RNAi to knock down the caffeine-producing genes in a coffee plant has stimulated abundant interest. The authors, Shinjiro Ogita and colleagues at Japan's Nara Institute of Science and Technology, described their successful growing of transgenic coffee plants of the species Coffea canephora in which RNAi suppressed the gene that encoded theobromine synthase, one of three N-methyltransferase enzymes responsible for caffeine biosynthesis in coffee plants.  They found that the caffeine content of the plants was 70 percent less than non-transgenic plans, suggesting the feasibility of producing caffeine-deficient coffee beans.


Another significant RNAi-related paper published in recent days is the June 19 article in FEBS Letters (The journal of the Federation of European Biochemical Scientists), in which a group from Berlin's Humboldt University Institute of Pathology used siRNA to inhibit the clinically important MDR1 gene responsible for multidrug resistance in lines of pancreatic and gastric cancer cells. The siRNAs, they reported, inhibited the MDR1 expression as much as 91 percent at both mRNA and protein levels, and decreased resistance against the drug daunorubicin. This research could potentially lead to use of siRNA as a co-therapeutic that makes some multidrug resistant tumors sensitive to drug treatment, they said.

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