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Nastech Breaks Out New RNAi Technologies, Evades Questions About Possible Deal for Dicer-Substrates

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Nastech Pharmaceutical provided details on its RNAi drug programs to the financial community last week, highlighting its influenza program and detailing two new RNAi-related technologies it has been developing.
 
Nastech also said during an analyst and institutional investor day that it is investigating the use of 27-mer RNAi duplexes, also known as Dicer-substrate siRNAs, as potential therapies, suggesting that the company may have struck a licensing deal with City of Hope, which holds the rights to the technology for diagnostic and therapeutic applications.
 
During a presentation largely geared for an audience unfamiliar with RNAi, Nastech CSO Paul Johnson provided a brief overview of Nastech’s RNAi programs in influenza, which was acquired through the company’s purchase of the RNAi assets of Galenea earlier this year (see RNAi News, 2/23/2006), and its program in rheumatoid arthritis. 
 
While he did not offer timelines for the programs, Nastech President and CEO Steven Quay told RNAi News this week that the company is on track to file an investigational new drug application for its flu candidate, G101, sometime early next year — just slightly beyond his previous expectation of an IND filing “near the end of [this] year.”
 
“We’re interested in developing drugs, not just filing INDs,” Quay said. “Sometimes it takes a little bit longer, but if your focus is drug approval it’s sometimes worthwhile to do that.” He added that Nastech is still scheduled to begin phase I testing an RNAi-based drug candidate for RA in the first half of 2007.
 
Also during the analyst and investor event, Johnson highlighted Nastech’s development of two new technologies: one, nicknamed ribo-t for ribothymidine, which appears to confer stability and specificity to RNAi molecules, and a delivery approach combining peptides and lipids.
 
“Typically, the kind of modifications [commonly used]… are very good at stabilizing siRNAs in the blood, but they often have a very detrimental effect on the potency of the molecules,” Johnson said last week. However, the company has found that selective replacement of a uracil with a thymidine can improve chemical and temperature stability of siRNAs.
 
“We’ve also discovered that [the] somewhat modest but defined increase in stability [Nastech has observed] has the effect of actually increasing the activity of the siRNA, because when the antisense strand of the duplex siRNA binds to the messenger RNA, it binds more strongly,” he said.
 
Johnson also noted that GU wobble base pairing is not uncommon in RNA and gives “an siRNA you’ve designed against a certain target … a little bit of promiscuity with what it binds to,” which can lead to off-target effects. Therefore, the use of a ribo-t modification can “tighten up [an siRNAs] selectively.”
 
As for Nastech’s work on new delivery approaches, Johnson said that “one of the major discoveries over the past year … is [the] unexpected synergistic effects between certain peptides and certain lipids.”
 
On their own, lipids do a good job of protecting siRNAs from degradation in the bloodstream and are endosomolytic, he said, but “they can be extremely toxic.” Peptides, meanwhile, offer a high level of cellular uptake with low toxicity while stabilizing siRNAs, but if “designed improperly, they don’t always have very good endosomolytic properties” and can be potentially immunogenic.
 
According to Johnson, Nastech researchers have found that certain types of peptides and lipids, which are not very effective for siRNA delivery on their own, “in combination [lead to] very effective knockdown. The combination is very potent,” he said.
 
Quay told RNAi News that these two technologies, in particular ribo-t, are so promising that the company is using them in its influenza and RA programs. Additionally, Nastech is considering out-licensing opportunities with other RNAi drug firms — and not just deals in indications it isn’t exploring itself.
 
“Because RNAi is not the only thing we’re doing at this company, we’re going to take a broader approach in terms of licensing and being less restrictive in our licenses,” he said. “There are fields where a widely available technology, if applied broadly, can make a very successful business model — this may be one of those.
 
“At the end of the day,” Quay added, “if Nastech had every FDA-approved RNAi [drug] with some of our ribo-t and peptide [technologies] in them, we’d be very happy.”
 
Deal for Dicer-Substrate?
 
A major portion of Johnson’s presentation dealt with Nastech’s use of Dicer-substrate siRNAs and the benefits of these molecules.
 

“Typically, the kind of modifications [commonly used]… are very good at stabilizing siRNAs in the blood, but they often have a very detrimental effect on the potency of the molecules.”

The technology — which was developed by researchers from the City of Hope’s Beckman Research Institute, COH, and Integrated DNA Technologies — uses synthetic RNA duplexes between 25 and 30 nucleotides long to trigger RNAi silencing.
 
According to a paper published last year in Nature Biotechnology, initial work by researchers from COH and IDT indicated that 27-nucleotide long RNA duplexes could be up to 100 times more effective at silencing genes than conventional 21 nucleotide-long siRNAs without inducing an interferon response or activating protein kinase R in cells.
 
A little more than a year ago, IDT exclusively licensed the Dicer-substrate technology for functional genomics and research applications from the Beckman Research Institute, leaving the diagnostic and therapeutic rights to the 27-mer siRNAs in the hands of COH (see RNAi News, 7/15/2005).
 
According to Brian Clark, director of the office of technology licensing at COH, the institute was exploring possible licensing deals for the technology with a number of RNAi drug shops.
 
Nastech’s public discussion of its work with 27-mer siRNAs, as well as its use of the Dicer-substrate moniker, strongly suggests that it may have acquired certain rights to the technology from COH.
 
Both Quay and Clark declined to comment this week on the existence of any such deal.

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