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Nobel prize winners compete, and drug development may benefit

Two Nobel Prize winners, each working with his own biomedical company in the Boston area, are racing to turn a 10-year-old genetic discovery into novel therapies that may help drug development at major pharmaceutical companies.

By John Lauerman

BOSTON: Two Nobel Prize winners, each working with his own biomedical company in the Boston area, are racing to turn a 10-year-old genetic discovery into novel therapies that may help drug development at major pharmaceutical companies.

Phillip Sharp, founder and chairman of Alnylam Pharmaceuticals, and Craig Mello, a co-founder of RXi Pharmaceuticals, are seeking to be the first to use a technology called RNA interference, or RNAi, which blocks the actions of genes. RNAi's potential against almost any disease may lead to drugs with sales "in the billions," said Ding Ding, an analyst for Maxim Group in New York.

Sharp, who won the Nobel in 1993, has seen shares of Alnylam Pharmaceuticals triple in value since 2004 on research indicating that the technology may lead to therapies against infectious diseases, cancer and arthritis. Alnylam's licensing deals with Merck, Novartis and 23 other drug makers could bring the company $1 billion in royalties.

Pfizer, the world's largest drug company, is also investing in the new approach.

"This is really something revolutionary, and nothing has blown it out of the water yet," said Judy Lieberman, a biochemist at Harvard Medical School in Boston. "It provides the chance to target all the so-called nondruggable targets. It opens up a universe of molecules you can intervene with."

As scientists have gained more knowledge of the role of genes in disease, the promise of RNAi has grown. Viruses, for example, are composed almost entirely of genetic material and cancer is principally a disease of flawed DNA.

By turning off certain genes through the process of RNAi, scientists are attempting to squelch the biological machinery that drives illnesses as varied as bird flu and AIDS.

"Over time, we see the potential for treating or curing some of the most horrendous diseases known to man," said Steven Kriegsman, chief executive officer of RXi's parent company, CytRx, based in Los Angeles. "The sky's the limit."

There have been other DNA-based treatments that have fallen short when tested extensively in humans. Gene therapy, after much promise, proved to be a failure for treating diseases. Side effects, which might still crop up in tests, and particularly the problem of introducing the treatment molecules into cells, might similarly delay RNA interference drugs from reaching the market, Ding said.

"We still have so little experience with RNAi," Ding said. "I think we will get there. The question is whether it will be 10 years before we have significant products, or more like 20 or 30 years," she added.

Mello and Sharp are betting that the time span will be shorter.

Sharp, a biochemist at the Massachusetts Institute of Technology, won his Nobel for discovering how cells splice genes together to make the protein chemicals that carry out the functions of life.

Mello did the initial work on RNAi in animal studies in 1998. He was awarded his Nobel prize for the advance last year and helped found RXi this year.

Sharp and Mello have drafted top scientists from a relatively small field of experts, many of whom they have worked with before. Prized qualities are scientific acumen, patents and an idea for how to get RNAi drugs into tumors, the liver, lungs, eyes or other tissues where they can do the most good.

Sharp, for instance, recruited Tom Tuschl, a former student, into Alnylam, bringing along exclusive rights to a patent called Tuschl 2. That gives the company control over use of so-called siRNA's, which are strands of genetic material that researchers say may form the basis for drugs.

Alnylam's licensing deals with drug makers like Merck and Novartis are providing critical research funds. RXi has no such licenses. Alnylam is near MIT and Harvard in Cambridge, Massachusetts, and has about 120 employees, many from the two nearby universities. RXi, based in Worcester, Massachusetts, 40 miles, or 65 kilometers, away, has fewer than 20 employees.

Sharp founded Alnylam in 2002, three years after reading a paper written by a former student of his, Andrew Fire, who would share the 2006 Nobel with Mello. In that paper, Fire showed how feeding RNAi molecules to nematode worms had blocked their genes from producing proteins.

Sharp said he had been stunned by the implications. "I understood that this was really a very general biological phenomenon," Sharp recalled. "It was ancient and broad and deep and powerful, and no one had ever recognized it. It had to be a fundamental principle."

Even one-celled algae use RNAi to turn off genes when they need to stop making certain proteins or stop a biological process, researchers at the John Innes Center in Norwich, Britain, have found. That suggests that RNAi evolved as part of a molecular on-off switch millions of years sooner than multicelled plants and animals themselves, they said in a study published last month in Nature.

Big drug makers see the possibilities, too. After paying $1.1 billion for Sirna Therapeautics, a rival to Alnylam, in January, Merck said it planned to spend $1 billion more to develop RNAi drugs over the next five to 10 years.

"It's a game changer for Merck," said Alan Sachs, vice president of RNA therapeutics for the company, which is based in New Jersey. "It's a big-investment, big-win type of scenario."

Pfizer has a two-year agreement to work with closely held Mirus Bio, based in Madison, Wisconsin, to research RNAi in animal models. The company plans to become involved in drug development.

"At Pfizer, we are determined to be a major player and a significant component of the RNAi community," said Tom Turi, director of translational biomarkers and mechanistic biology for the company. Pfizer may license technology, acquire a drug developer or develop its own drugs, he said.

That is a good move, Sharp said.

RNAi is "the next great product platform for the development of new therapeutics," he said. "It's the revolution of the decade."