Editor

Like making good soup, bringing laboratory discoveries to the point where they are useful to biotechnology typically takes a long time - and the science of RNA interference, or RNAi, is just about ready to dish up.

Ribozyme Pharmaceuticals Inc. put RNAi on the front burner 18 months ago. Earlier this month, the company went further still, proposing to raise $48 million through an RNAi-based deal with prestigious investors who would take control of RPI if the agreement wins approval. Not bad for a Boulder, Colo.-based company whose stock was selling last week at less than 50 cents.

The terms call for the sale of stock and warrants to a group including The Sprout Group, Venrock Associates, Oxford Bioscience Partners, Techno Venture Management, and Granite Global Ventures, which would get the right to appoint four board members to RPI's seven-person board, thus gaining a controlling interest.

RPI shareholders must give their blessing to the deal, along with a reverse stock split, and are expected to do so in April, said Howard Robin, RPI's president and CEO, who said the company has a "clear leadership position in the RNAi world." RPI has filed 50 patent applications in the field and 30 have been issued for the chemistry, stabilization and synthesis necessary to use the RNAi approach.

"Non-stabilized RNAi has a very short half-life, on the order of seconds, and doesn't have very important value as a therapeutic," Robin told BioWorld Financial Watch. "To date there's one U.S. patent [the Carnegie Institution of Washington] and one in Europe. Outside of those, we know of no other patents that have been issued. This will become very important," since RPI's stabilization patents will give it an edge.

The Carnegie research 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., Europe and Japan.

RNA is known for carrying DNA's 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.

What it means is that the technology might be useful in shutting down a gene that causes disease, or at least in helping researchers find pathways for potential drugs.

Other scientists at UMMS are working in RNAi. One project is examining the biochemical machinery through which it operates by using extracts from fly embryos and human cells. Another targets a particular form of RNAi, called small interfering, or siRNA, for its potential role in blocking HIV infection.

Such efforts are a long way from drugs, though, and here again RPI claims an advantage. The firm has programs in hepatitis C and macular degeneration, with targets also in diabetes, obesity, oncology and central nervous system disorders such as stroke. Robin said the company is "looking to approach the clinic in 2005."

Other companies are making forays into the area. Intradigm Corp. this month said it successfully employed its Efficacy-First method to discover and validate five human cancer drug targets directly in human xenograft tumor models, using in vivo RNAi delivery. The news came during a San Diego conference devoted solely to applications of RNAi; another, focused on siRNA, is slated for March in La Jolla, Calif.

"Everybody's starting to recognize that RNAi already established itself as very important in the field of target validation," Robin said.

In November, Cell Therapeutics Inc. offered preliminary cellular and animal model data on a cancer target developed with RNAi. Overseas firms got into the act. Compugen Ltd., of Tel Aviv, Israel, last year expanded a collaboration with Novartis AG to add RNAi, and the Netherlands-based Qiagen NV bought the U.S. firm Xeragon Inc., a provider of products and services for synthetic RNA and RNAi.

Some firms are teaming up with non-commercial researchers in various ways. Alnylam Pharmaceuticals Inc. licensed RNAi patents this month and OSI Pharmaceuticals Inc. entered a research deal with Cold Spring Harbor Laboratory to use the latter's RNAi technology platform in cancer drug discovery programs. Illumina Inc. in December entered an agreement with Cold Spring to provide nearly 100,000 longmer oligonucleotides for the lab's ongoing work. A large-scale study is designed to determine the mechanism of RNAi, and Illumina said it was using its Oligator high-throughput DNA synthesis facility for the project.

"These companies' [programs] are pretty much in a start-up mode, and they will encounter all the problems and challenges we have already encountered and solved," Robin said.

RPI plans to go full bore on its research, boosted by the latest financing, while deliberating with partner Chiron Corp. how to proceed with their Phase II anti-angiogenesis drug Angiozyme for metastatic colorectal cancer. Last spring, a Phase II trial with the drug in metastatic breast cancer failed to achieve a clinically significant response rate.

Another RPI drug, Heptazyme, hasn't fared well, either. RPI last year stopped dosing in a Phase II trial of Heptazyme after an animal from a preclinical study lost its vision, a stock-punishing piece of news. RPI said it was replacing its original formulation of Heptazyme with a second-generation version, which was expected to enter clinical trials in 2004. That probably won't happen now, Robin said.

It also was last year that RPI restructured, decreasing staff from 120 to 90, to focus on RNAi. "We didn't shift into this area because of investor desires," Robin said, or as part of a last-ditch effort to keep the company viable.

"Quite the contrary," he said. "We [asked], What does it take to change direction and move in an area that's within our field of expertise? Where does the skill set in RNA chemistry lead us?'"

The skill set led them to RNAi. Nassim Usman, chief scientific officer and vice president of research and development for RPI, said "the reason you see so many institutions taking credit [for RNAi] is that it's such a potent mechanism that it's being used all over the place."

But the Carnegie patent based on the 1997 work "covered very long double-stranded RNA molecules and could only be applied to worms and plants," he told BioWorld Financial Watch. "That's not a practical way to approach making a drug for humans."

If RNAi needed more vindication, it gained some recently when the journal Science voted the discovery of small RNA molecules and their role in RNAi the 2002 scientific breakthrough of the year.

RPI's group of investors only had to study RNAi to find the value, Robin noted.

"They're very high caliber," he said. "They've done an awful lot of homework."