This story has been corrected from a previous version that incorrectly referred to Sirna Therapeutics instead of Alnylam. RNAi News regrets the error.
As might have been expected, the need for potent siRNAs for RNAi research and effective delivery methods for therapeutics were two of the underlying themes of many of the presentations at the Nucleic Acid World Summit in Boston this week.
For the research side, David Dorris, manager of custom RNA services at Ambion, said in his presentation that having potent siRNAs offers benefits beyond the obvious lengthened duration effect. After all, a longer knockdown can oftentimes be obtained by increasing siRNA concentration. But with a highly effective siRNA, he said, a researcher needs a lower concentration of the oligo to achieve a desired effect, which will help to cut costs, reduce off-target effects, and allow for the combination of multiple siRNAs in order to target several genes at once.
Identifying the need for more potent siRNAs is one thing, but designing them is another. While most rely on the fundamental Tuschl rules to guide them, a new approach, being undertaken at Amgen, involves looking to microRNAs for clues.
Amgen researcher Sumedha Jayasena said that the company has started modeling its synthetic siRNAs after these naturally occurring miRNAs, given that the two act similarly and share a common pathway in Dicer. He said the approach has yielded encouraging results, but noted that it is a new one and doesn’t offer a complete solution. “Nothing is 100 percent,” he told RNAi News.
As important as siRNA design is, once one starts looking to RNAi for drugs, the question is how to get good siRNAs into the body.
BD Biosciences Clontech research scientist Brad Scherer said that his company is trying to use viruses to solve the problem. Scherer said that viral expression systems have many benefits, such as high infection efficiency, high expression levels — especially with adenoviral vectors — stability, and heritable expression, with retroviral vectors.
Gary Van Savage, director of technology licensing at Johnson & Johnson, agreed with Scherer in one respect, commenting later during the conference that “the hurdle is not RNAi; the hurdle is transfection.”
But as for viral delivery, Van Savage said that Johnson & Johnson, already cautious about the technology for purposes other than target validation, is not even considering viral vector approaches due to concerns over antibody responses, potential patient immunity, toxicity, and trouble with the FDA in light of the problems with gene therapy.
Others appear to agree. Mirus, for example, is attempting to deliver nucleic acids using intravascular and intravenous injection procedures. Such methods, which have been used to transfect liver cells in mice and pig heart cells, carry a lower cost and a reduced risk of toxicities than viral delivery methods, according to Mirus senior scientist David Lewis.
Alnylam, too, is looking at non-viral delivery, trying to mix siRNAs with agents such as cationic lipids, nanoparticles, and liposomes. The company is also exploring, though less actively, delivering siRNAs with devices such as drug-coated stents and in aerosol formulations, according to CEO John Maraganore.
Another key topic at NAWS was the challenges facing RNAi-based therapeutics developers in raising awareness of their technologies with potential partners.
Van Savage, appropriately speaking on the subject, suggested that companies consider looking to scientists rather than technology licensing execs. This is certainly how Alnylam found its opportunity, albeit indirectly; The company was approached by Merck over striking their new research collaboration largely on the urging of Merck senior vice president of molecular profiling and cancer research Steve Friend, who has been close with Alnylam co-founder Phil Sharp for years.
By getting its researchers to talk to their counterparts at larger companies, a small RNAi firm may increase its odds of raising awareness about its technology, he said, noting that Johnson & Johnson has about 40 people in its business development unit, but thousands of researchers who often attend trade shows and conferences like NAWS.
Van Savage said that quite frequently it is Johnson & Johnson’s scientists who come to his department with leads. “They tell us what they like, and that’s the best way,” he said.