Biotech's Hope Isn't Just DNA Anymore

RNA is showing promise, too, from cancer to AIDS

Like many young biotech companies, Ribozyme Pharmaceuticals Inc. (RZYM ) struggled through its early years, piling up millions in losses without producing any new drugs. Investors lost faith, pushing its stock to less than 30 cents a share late last year. So it was a bit of a surprise when the 11-year-old Ribozyme announced on Feb. 12 that venture capitalists had snapped up $48 million worth of stock and warrants, effectively taking control of the Boulder (Colo.) company.

Why shell out so much for a troubled drug developer? Because Ribozyme has refocused its research on an experimental cell-based therapy that scientists call one of the biggest biological breakthroughs of the last two decades. The mechanism it seeks to exploit may amount to an off-switch for some disease processes in human cells. Scientists activate the switch by introducing small double strands of RNA, the same messenger molecules that translate DNA code into proteins. Knowledge of this process, called RNA interference (RNAi), is so preliminary that, until two years ago, the technique worked only in plants, worms, and fungi.

Since then, RNAi has swept science faster than a cold virus. Pharmaceutical companies and labs worldwide are using it as a tool to help find better targets for drugs to attack. Venture capitalists are pouring in cash, in the hope they have discovered a magic bullet for treating diseases from hepatitis C to cancer to AIDS. New biotech companies are scrambling to develop drugs based on the technique, and some older ones such as Ribozyme are shifting to embrace it. "It's revolutionizing science," says Gary Ruvkun, a professor of genetics at Harvard Medical School.

It all started in 1989 with a purple petunia. Richard A. Jorgensen, then a researcher at Advanced Genetic Sciences in Oakland, Calif., thought he could brighten up the blossoms by adding a pigment gene. Imagine his surprise when the genetically engineered flower bloomed white instead. What at first seemed like a bungled experiment turned out to be a lucky break that showed RNA was more than a faithful messenger for genes. It could actually block the messages, preventing the production of potentially harmful proteins triggered by viruses or cancer.

It took more than a decade to duplicate the feat in mammals. The clincher: using short strands of RNA instead of long ones. Members of Thomas Tuschl's lab at the Max Planck Institute in Gottingen, Germany, presented their results with the short strands at a 2001 scientific meeting--and nearly floored the crowd. "There was this stunned reaction because the audience understood the ability to do science in mammalian cells had just changed," says David R. Engelke, professor of biological chemistry at the University of Michigan.

That may be true, but some scientists say it's early to make the leap to new RNAi-based drugs. Researchers still must prove they can deliver double strands of RNA to billions of cells. Once they find a way in, they have to be able to target messenger RNAs consistently and effectively, without harming the patient. With those challenges ahead, scientists predict it could take 10 to 20 years to bring an RNAi-based drug to market.

What sways the true believers, however, is that RNAi techniques yield results in so many labs. Researchers who heard the presentation two years ago rushed home and easily duplicated the experiment. And in vitro, at least, the technique seems more potent than earlier RNA-based approaches. "RNAi's potential for therapeutic use has great promise," says Dr. William A. Haseltine, chairman of genomics pioneer Human Genome Sciences Inc. (HGSI )

Ribozyme is one of several players taking up the challenge. With new cash from Oxford Bioscience Partners, the Sprout Group, and others, it hopes to develop RNAi treatments for hepatitis C and macular degeneration, an eye disease. Nobel prize winner Phillip A. Sharp, Tuschl, and colleagues--all early leaders in RNAi discoveries--last year co-founded Alnylam Pharmaceuticals in Cambridge, Mass. They've raised $17.5 million to pursue therapies for viruses, cancer, and autoimmune diseases from Polaris Venture Partners and Cardinal Partners, among others. German startup Ribopharma is targeting pancreatic cancer and malignant melanoma. Meanwhile, Big Pharma is keeping a close eye on their progress.

Though the hurdles are high, they can be cleared. "These are some of the better people in the industry, with a lot of money," says Geoffrey Duyk, chief scientific officer of Exelixis Inc., a biotech company in South San Francisco that uses RNAi in research. And they have come a long way from petunias.

By Faith Keenan in Boston

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