National Editor

Joining the firms aiming to use RNA interference in their drug-making efforts is the delivery company Nastech Pharmaceutical Co., which has gained a worldwide, nonexclusive license to key RNAi patents from the Carnegie Institute for an undisclosed payment.

Steven Quay, president and CEO of Bothell, Wash.-based Nastech called the science behind the "Fire" RNAi patents and patent applications, as they are known, "foundational" and likened it to the research into monoclonal antibodies and recombinant DNA.

"I've been in the company three years, and it's been part of the research effort since I came here," Quay said.

Nastech's stock (NASDAQ:NSTK) closed Monday at $9.25, down 22 cents.

Under the license, Nastech plans to use the small interfering RNA technology in tight junction research and to develop therapeutics based upon siRNA technology. Tight junctions are cell-to-cell connections in the epithelial and endothelial layers.

"They're the mechanism by which tissues are held together," Quay said. "The cells are touching each other laterally on the sides, and the tight junctions give them tensile strength so you can't just pull them apart. They were [once] thought to be just cement holding the epithelium together, but in fact they're sort of a gate," allowing "immune traffic" and other interactions between cells, he said.

Quay told BioWorld Today he has "kind of retooled the company's direction, and we believe we're the only drug delivery company using molecular biology and pharmacology, and treating the tight junctions as pharmaceuticals targets."

He likened the firm to Mountain View, Calif.-based ALZA Corp., a unit of New Brunswick, N.J.-based Johnson & Johnson, which was "founded as drug delivery focused but used physical chemistry as their tools. ALZA solved a lot of problems but has left some unsolved."

SiRNAs are double-stranded RNA molecules, 20 to 22 nucleotides in length, that can silence a single gene in a sequence-specific manner by degradation of the target messenger RNA. Nastech hopes to identify which tight junction proteins are the most appropriate targets to modulate function, and better deliver drugs.

The Carnegie research behind the patents licensed by Nastech dates back to 1997, when Andrew Fire at Carnegie and Craig Mello of the University of Massachusetts Medical School found that by designing RNA with two strands they could silence targeted genes. Since then, the patented method has been licensed in the U.S. and abroad.

RNA carries DNA code from the nucleus of a cell to ribosomes, where proteins are made. The first strand of specially designed RNA bears the ribonucleotide sequence matching the nucleotide sequence in the targeted gene, and the second strand bears a sequence that is complementary to the target gene. Together the strands degrade a specific messenger RNA, thus inactivating the gene.

"For competitive reasons I would not like to talk about targets," Quay said, although other companies are going after the likes of cancer and viral infections using the technology.

With RNAi as a field heating up, are legal battles ahead for the firms involved?

"There are a few competing patent applications or issued patents, but it's a little hard to tell at this point how overlapping they will appear," Quay said. "Part of that is how good a job the patent office does at prosecuting patents and allowing claims." The office has "been through gene splicing, monoclonal antibodies and therapeutic proteins. The patents are all getting better."

Nastech's furthest-along product is apomorphine for erectile dysfunction. The drug is a dopamine agonist and works by a different mechanism of action than the phosphodiesterase Type 5 inhibitors, such as Pfizer Inc.'s Viagra (sildenafil citrate) and its competitors. Specifically, apomorphine stimulates the D1/D2 class of dopamine receptors in the brain responsible for beginning an erectile response. Oral ED drugs can take up to 90 minutes to act; apomorphine acts in 10 to 15 minutes.

"We're doing a maximum tolerated-dose study, where we keep raising the dose and looking for toxicity," Quay said. Data are expected in the second quarter.

Nastech also has filed an application to market its formulation of intranasal calcitonin for osteoporosis, and the company's morphine gluconate for breakthrough pain is in Phase II, but Quay said that, in terms of commercial opportunity, "I think apomorphine [for ED] comes out ahead."