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BioDelivery Tech Used to Deliver Flu-Targeting siRNAs; Company Eyes Other RNAi Approaches


North Carolina-based BioDelivery Sciences said this week that outside researchers have used its Bioral drug-delivery technology to deliver siRNAs targeting H5N1 avian influenza genes both intravenously and intranasally into a mouse model.
The work, which was conducted by an undisclosed “commercial collaborator,” marks BioDelivery’s most mature effort to date to apply its technology to the burgeoning RNAi drugs sector.
According to BioDelivery, in preclinical tests a single intranasal dose of an siRNA delivered with the Bioral technology four hours after influenza exposure cut viral titers in the lung by 200 percent. When delivered intravenously, the Bioral siRNAs were about 25 times more effective in reducing viral levels compared with naked siRNA, the company added.
Additional details about the research were not disclosed.
Based on the positive results from this preclinical work, the unnamed collaborator is set to conduct additional research to evaluate the Bioral technology, Mark Sirgo, president and CEO of BioDelivery, said.
“The outcome of that work will determine how far we go with them” and whether a formal licensing deal is signed, he added.
Sirgo declined to provide details about BioDelivery’s collaborator, but its interest in siRNA-based therapeutics for influenza suggests at least two possible RNAi drug players.
One is Nastech Pharmaceuticals, which recently began working on an siRNA-based treatment for the virus after it acquired the RNAi assets of Galenea (see RNAi News, 3/2/2006). The other is Alnylam Pharmaceuticals, which has also been developing an RNAi-based therapy for pandemic influenza and recently signed a deal to work with partner Novartis on the program (see RNAi News, 2/23/2006).
Raphael Mannino, founder and CSO of BioDelivery, noted that the Bioral technology has also been evaluated by at least three other firms for RNAi drug delivery beside the one that conducted the influenza work, and Sirgo said that the company’s strategy is to find licensees for the technology on an indication-by-indication basis as much as possible. 
Sirgo said that BioDelivery has not ruled out the possibility of developing its own RNAi drug using the Bioral technology down the road, but that “currently our feeling is that we’d prefer to partner with companies that … have a large stake in the intellectual property around these siRNAs.”
“There is such an intellectual property situation going on right now with siRNAs that we would look to probably partner with people that have a proprietary position either with a sequence or within an indication,” Mannino added.
The Technology
The Bioral technology involves the encapsulation of a drug within an ahydrous, nanocrystalline structure called a cochleate to prevent degradation within the body.
“With siRNAs or any [other] RNA therapeutics, one of the main challenges is finding a way to protect the [drug] from degradation by the ribonucleases that are present on skin, in plasma, [and] in muscosal secretions,” Minninos said. “Cochleates, number one, can do that — they can hide the drug and protect it.” It isn’t until the crystal reaches the inside of a cell that it delivers its payload, he said.
“The reason why the crystal is stable is because it’s held together by calcium, and there is enough calcium in plasma and interstitial fluid [and] mucosal secretions that the crystal remains a crystal,” Minninos explained. “However, the concentration of calcium inside cells is very low. So once the crystal goes into the cell, the calcium begins to be removed by the cell, the crystal opens, and then delivers its contents to the inside of the cell.”
Minninos said that the Bioral technology also allows drugs to be delivered in a somewhat specific manner.
“At this point, it appears that the tissues that take [the crystal] up are tissues that in some way or another have an inflammation or infection,” he said. “We’ve been able to show in animal models [of] inflammatory diseases and infectious diseases that there appears to be an uptake of the drug crystal by activated cells — either virally infected cells or activated macrophages or neutrophils.”

“There is such an intellectual property situation going on right now with siRNAs that we would look to probably partner with people that have a proprietary position either with a sequence or within an indication.”

BioDelivery is also contemplating more approaches for more specific delivery, such as through the attachment of targeting ligands to the surface of the cochleates, but “we haven’t begun testing [this] on a wide-scale,” Minninos said. “We actually have a patent application describing our ability to do that with the cochleates, we just have not done it yet.”

According to Minninos, the Bioral technology has shown to be non-toxic in oral, intravenous, and intranasal formulations, in part because it is made up of safe, naturally occurring compounds — namely phosphatidylserine, which is available over-the-counter in the US as a nutraceutical, and calcium.
Additionally, the cochleates are inexpensive to produce, Minninos said. “A number of the things over the years that have been used to deliver nucleic acids have turned out to be toxic or very expensive,” he said. “Our raw materials are very inexpensive, relative certainly to an RNAi molecule, and our toxicity is very low.”
Getting in on the Action
Like a number of other companies currently shopping their delivery technology to the RNAi drugs marketplace, BioDelivery originally developed the Bioral technology for other purposes.
When the company originally developed the cochleates to deliver biologically active molecules in the early 1990s, “we were working on vaccines, and one of the molecules we were working with … were DNA plasmids,” Minninos said, adding that the company also experimented with delivering an antisense molecule. However, “the efficiency and the reproducibility of getting the nucleic acid into the cochleate was not what one would need for a commercial product.
“About a year and a half ago, when we began to see increased interest in things like siRNA, we began to re-visit the interaction between cochleates and nucleic acids based on a lot of the work we had done on small-molecule drugs,” he said. “What we developed … is a very reproducible, high-efficiency methodology for getting oligonucleotides, including siRNAs, into the cochleate crystal, [which] was our incentive for trying to find partners to help them solve their problem of protection and delivery.”

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