Atugen said this week that it has expanded its focus beyond drug discovery and target validation to include RNAi-based therapeutics, a move CSO Klaus Giese said was a natural progression from the company’s work with gene-silencing technologies.
Atugen has long been conducting target validation work for biopharmaceutical partners, including AstraZeneca and Schering, using its antisense, RNAi, and ribozyme technologies. In the process, Giese told RNAi News, the company has also developed novel siRNA molecules — and secured related patent protection — so that it became “obvious that we’d have to enter into the therapeutics arena.”
These siRNA molecules, he said, are different from traditional siRNAs in several respects: “They have no overhangs. Normally siRNAs have 3’ overhangs [but] these are blunt-ended molecules.” Additionally, “they are composed of ribonucleotides only — conventional siRNA molecules are chimeric [oligos] of DNA and RNA.”
Importantly, Giese said that Atugen’s siRNA molecules also contain proprietary modifications that “make these molecules nuclease resistant [and] stable in circulation.” He declined to comment specifically on stability data from in vivo studies of the siRNAs, but noted that “in vivo, we have a clearance [of the siRNAs] but … so far we don’t know if they are secreted or if they are actually taken up.”
He noted that after “20 minutes, we cannot see them anymore in circulation, [but] probably it’s not degradation — you have the liver, the kidney, and [so we] don’t know where these molecules end up at the moment.” Giese added that in vitro experiments indicate that the molecules are stable for at least 24 hours.
Based on the data that has been gathered, Giese said that Atugen plans to focus its RNAi-based therapeutics efforts on treatments delivered systemically to the liver and topically to the skin.
“For the liver, we have actually done the first proof-of-principle [study] for biological activity using a molecule that is involved in glucose uptake — it’s an insulin sensitizer experiment where we could show that we have an accelerated uptake of glucose from the bloodstream after the application of our siRNA molecules in vivo,” he said. “Now, we’ll probably be going for liver cancer and other liver diseases.”
While Giese did not disclose what other liver indications Atugen is targeting, he did state that hepatitis would not likely be one because viruses such as hepatitis and HIV “have a high mutation rate and siRNA molecules require 100 [base-pair] matching for activity. So, he added “we feel that with this kind of technology, siRNA viral therapy might not be suitable because of the high mutation rate — you might need a mixture of many different siRNA molecules” to make an effective treatment.
For dermatological indications, Giese said that his company is looking at wound healing, and that indications such as psoriasis might be considered down the road should the technology prove effective.
He said that Atugen is currently exploring wound healing applications with researchers at the Swiss Federal Institute of Technology (ETH), Zurich. Part of the collaboration, he noted, is evaluating the company’s proprietary liposomal delivery technology that is designed to carry the siRNA molecules to different layers of the skin.
In terms of targets the company is looking at for wound healing, Giese said that these would depend on how deeply the siRNAs can be delivered into the skin, adding that “by targeting specific transcription factors of specific growth factors, you can prevent scarring and have an increased wound healing process.”
As for how Atugen plans to fund its RNAi therapeutics activities, Giese said that the company is in the middle of a financing round with a goal of raising between $5 million and $8 million. These funds would allow the company to survive for about two years, he said, and could allow it to begin phase I testing of an RNAi-based drug by the end of 2005.
Rather than going it alone, however, Geise said that Atugen would much rather find a large partner for its therapeutics programs, putting the company on the same playing field as Sirna Therapeutics, which recently inked a deal with Eli Lilly, and Alnylam Pharmaceuticals, which got the ball rolling with its Merck partnership. (See RNAi News, 1/30/2004 and RNAi News, 9/12/2003, respectively).
“We have a very good position in terms of intellectual property, we have stability of the molecules achieved, we have specificity achieved … and we’re on the forefront of delivery with our own liposomal formulations,” Giese said. “But we are a very small … and these molecules are really expensive.”
Preliminary discussions with possible partners have occurred, he said, but none have led to anything in-depth. When he spoke with RNAi News, Giese was in Vancouver at the Biopartnering North America conference — billed by its organizer as “a meeting place for investing in global partnerships” — where he said he was “exploring opportunities.”
Atugen is also in the process of putting together a company information package, he added, which will include available in vivo data from the siRNA experiments, for potential collaborators.