Blind World

Macular Degeneration.
Two firms stake their claims to RNAi, an emerging biotech category.

March 8, 2004.

By Matt Branaugh,
Camera Business Writer,
The Daily Camera.

If ribonucleic acid-interference, or RNAi, delivers what it promises, two Boulder-area companies believe they'll be at the forefront of scientific history and a substantial financial windfall.

But just what kind of history and what kind of windfall they'll realize isn't clear yet.

Many observers say RNAi, an emerging strategy that may lead to disease-fighting drugs, holds ample promise. Some, though, say RNAi smacks of past biotech promises along the lines of ribosomes or antisense that didn't deliver.

Lafayette-based Dharmacon Inc. and Boulder-based Sirna Therapeutics Inc. say they're banking on the former, ready to meet the challenges, grow and continue to push the boundaries of human biology, chemistry and medicine.

The stakes already are significant.

Dharmacon, and its RNA-based research tools, including a vast amount tied to RNAi, was acquired last month for $80 million by Fisher Scientific International Inc.

The publicly traded Sirna was on the verge of collapsing last year after years of failures as Ribozyme Pharmaceuticals Inc. It reinvented itself around RNAi work it had been developing for a couple of years, giving private investors an 85-percent ownership stake in return for $53 million to pursue potential drugs.

"We're the leader in what is probably the most exciting area in medical science," says Howard Robin, the president and chief executive officer of Sirna who spearheaded the company's "re-start," as he calls it. Rather than sell off the company assets, it made more sense to capitalize on its nucleic-acid experience, as well as a newly built on-site manufacturing lab, he adds.

That kind of enthusiasm has spawned dozens of like-minded companies and efforts worldwide. It's also garnered scores of media coverage, from Science magazine's "Breakthrough of the Year" in 2002 to lengthy pieces in The Wall Street Journal and Forbes magazine.

"It's huge," says Doug Macron, editor of the trade publication RNAi News, regarding interest in RNAi. "It remains to be seen whether it will be an effective therapeutic or not. The potential is there and if it translates successfully, you have a huge, huge discovery."

Here's the buzz surrounding RNAi: Human genes carry DNA, the body's entire set of instructions. Each cell type reads the portion of DNA tied to its specific function and generates specific RNA messages. In turn, the RNA messages are read and converted into the proteins the cell needs to fulfill its mission.

Think of the cellular process as a home construction project. The initial design of the home represents the DNA. Blueprints of the house then are generated from that design and taken to the site just as RNA messages are based on instructions from the DNA. Then, just like builders reading the blueprints and launching construction, the RNA messages begin converting into proteins.

Sometimes, mutations in the DNA cause the cell to produce too many messages, resulting in too much protein and uncontrolled cell growth the basis of cancers. Or sometimes the cell is influenced by an intruding bacteria or virus, like Hepatitis C, which forces the cell to produce viral proteins.

Thanks to some discoveries in the late 1990s, scientists say they've learned of a naturally occurring process in cells called RNAi. When the cell is operating normally, pieces of double-stranded RNA, also called short-interfering RNA, are used to silence expression of certain genes, meaning the cell already possesses an in-built mechanism to regulate its protein production or fend off intruders.

Here's where Sirna and Dharmacon come into play.

Dharmacon, founded in 1995 by Stephen Scaringe, makes the tools that allow researchers and companies to test genes to see what happens when they're silenced. Its clients include some of the pharmaceutical world's biggest Bayer Pharmaceuticals, for instance, just expanded an agreement to have siRNA reagents supplied for about 4,000 gene targets.

But Scaringe, who started the 100-employee company with nary a penny of outside investment as he wrapped up his doctorate work at the University of Colorado, says his company's strength goes well beyond RNAi.

"I saw RNA as one of the next frontiers, or next areas for significant upside potential," he says. "We're not sort of trapped or pigeon-holed into one application."

RNAi News' Macron says RNAi research's potential is already booming.

Creating drugs, like what Sirna is trying to do, is "a much bigger question," he says.

Sirna, a name that plays on short-interfering RNA, or siRNA, is trying to both identify genes at the root of diseases and find ways to introduce synthetically made siRNAs into the body to silence them.

The company already says it's found a way to get an RNAi compound that won't rapidly break down in the bloodstream, one of the big initial obstacles to using RNAi as a drug.

Barry Polisky, the company's vice president of research, says the technology holds promise. But the firm also realizes the struggles of predecessors.

Both Antisense, a 1980s discovery that still hasn't yielded a drug, and ribosomes used single-stranded RNA. The RNAi technique uses the siRNAs, which are double-stranded RNA and, scientists believe, better replicates the cell's natural mechanisms.

"We're very excited about the power of the technology. We understand other nucleic acid strategies have been developed over the last 10 to 15 years and we want to build on them," he said. "At the same time, we're well aware of a lot of the pitfalls."

The 70-employee Sirna believes its best first target is macular degeneration. The disease, found mostly among elderly with roughly 500,000 new cases worldwide each year, causes accelerated growth of blood vessels around the eyes, eventually causing blindness. Later this year, the company expects to file to begin clinical trials with the Food and Drug Administration.

While a macular degeneration treatment will likely get injected directly into the eye, the big question facing other potential RNAi-based treatments is figuring out how to get them into the correct part of the body to shut off the right gene without setting off some other unanticipated, unhelpful even dangerous reaction.

John McCamant and Cynthia Robbins-Roth, two biotech industry followers, say that uncertainty generates skepticism about the RNAi field's overall potential. Robbins-Roth, founding partner of California-based BioVenture Consultants, says RNAi research is the stronger of the applications right now.

McCamant, who edits the Medical Technology Stock Letter, is much harsher, calling RNAi "antisense junior." Without any candidates in clinical trials, it's impossible to gauge the value of companies pursuing the technology for potential drugs, he adds.

"No matter how sexy a technology is, it doesn't mean in its early stages it's going to translate into a proveable drug," McCamant says.

But Sirna's Robin remains upbeat. His company has enough cash for the next several years its burn rate, between $55 million and $60 million in 2001, will be $18 million this year to find out if RNAi will work.

Regardless of RNAi's long-term outcome, both Sirna and Dharmacon remain committed. A vast field of players, including the willingness of major biotechs to embrace RNAi, validates the opportunity even more, they say.

"At the very least, we're going to increase our knowledge, which can't help but help us in improving our lives," Scaringe says.

Contact Matt Branaugh at (303) 473-1363 or

Copyright 2004, The Daily Camera and the E.W. Scripps Company. All rights reserved.

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