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Study Is Setback for Some RNA-Based Drugs
  NY Times
Published: April 2, 2008
A NEW study is raising doubts about one of the hottest fields in biotechnology.
That field, called RNA interference, is supposed to provide a way to precisely turn off specific disease-causing genes. Biotech start-ups and big pharmaceutical companies are racing to develop drugs to harness this mechanism.
But the study suggests that at least some drugs now being tested in clinical trials actually work not by silencing genes but by activating the immune system. That could mean the drugs are not really precise tools and could have unexpected side effects.
"It seems to be working by a completely different mechanism that's unrelated to the underlying premise,h' said Dr. Jayakrishna Ambati, a professor of ophthalmology at the University of Kentucky and senior author of the study.
Dr. Ambati and colleagues from several other universities looked in particular at two drugs being developed to treat macular degeneration, a leading cause of blindness in the elderly, one by Opko Health and the other by Allergan.
The companies say that their drugs are safe and that they have their own evidence the medicines worked through the intended mechanism.
But those assurances did not necessarily calm investors. Shares of Opko had fallen nearly 10 percent since the study was published online by the journal Nature on March 26, before regaining much of that ground during Tuesday's broad market rally. Opko shares closed at $2.19, up 13 cents on the day, although still off 3 percent since before the Nature article appeared.
Shares of Alnylam, a start-up specializing in RNA interference, had been down more than 9 percent in the study's wake, closing on Monday at $24.40. On Tuesday, they rose 50 cents, closing at $24.90.
The stock of Allergan, a bigger, more diversified company that has $4 billion in sales of products ranging from Botox to breast implants, was not affected much. In fact, on Tuesday they closed at $59.55, up 4.8 percent from their March 26 close.
RNA interference is a natural mechanism used by organisms to render genes inactive - presumably the genes of invading pathogens. Two scientists who played a crucial role in discovering the mechanism won the Nobel Prize in 2006.
Companies are trying to make drugs that consist of short sequences of double-stranded RNA, the chemical cousin of the DNA in genes. The drugs are designed to activate RNA interference to silence a gene with a sequence of letters of the genetic code corresponding to the sequence in the drug. There are at least five such RNA drugs now in clinical trials.
The Opko and Allergan drugs aim to inactivate a gene that contributes to the formation of leaky blood vessels in the back of the eye, the hallmark of the severe form of macular degeneration.
But Dr. Ambati and his team found that virtually any sequence of RNA, not just the ones in the drugs, worked equally well in stopping blood vessel formation in the eyes of mice. They tried RNA sequences corresponding to other mouse genes, to a jellyfish gene, to a firefly gene. They also tested a completely random RNA sequence. All worked.
The reason, Dr. Ambati said, was that the RNA snippets were actually binding to an immune system sentry called toll-like receptor 3. That aroused the immune system, setting off a chain of events that stopped the blood vessel formation. He said the research showed that the drugs were not even getting into the cells in the eye, so they could not be activating the gene-silencing mechanism.
As further confirmation, Dr. Ambati's team used genetically engineered mice that lacked the immune system sentry. In those mice, the drugs did not work.
Dr. Ambati said the findings raise the question of whether RNA drugs for other diseases could also set off similar immune responses, perhaps stopping formation of necessary blood vessels or causing other undesirable side effects.
Dr. Ambati is a scientific adviser to Allergan and to Quark Pharmaceuticals, another company working on RNA interference. The study, however, was paid for by the federal government's National Eye Institute.
Samuel J. Reich, the executive vice president for ophthalmics at Opko, said the company's own data showed its drug did enter cells in the eye. He also said the drug did not leave the eye and enter the bloodstream, minimizing any risk of side effects.
The Opko drug, called bevasiranib, is now in the final stage of clinical trials, so it could be the first RNA interference drug to reach the market. It is the lead drug candidate for Opko, a Miami start-up company run by Phillip Frost, the billionaire who founded the generic drug company Ivax.
Caroline Van Hove, a spokeswoman for Allergan, said studies so far have demonstrated the safety of her company's drug, which is in the middle stage of clinical trials.
Other companies said the study's results would not necessarily apply to other RNA drugs.
"It's sort of like saying all birds don't fly when you are studying a penguin,h said John Maraganore, the chief executive of Alnylam, which is conducting clinical trials of an RNA drug to treat a respiratory virus. He said his company tested its drug candidates against other RNA sequences, to make sure that any effect was really from RNA interference.
Dr. Alan Sachs, the vice president for RNA therapeutics at Merck Research Laboratories, a unit of Merck, said that future versions of RNA drugs could be encapsulated in fat globules and chemically modified. That would help the drugs enter cells and keep them from setting off the immune system.
Merck paid $1.1 billion in 2006 to acquire Sirna Therapeutics, the RNA interference company that initially developed the drug being tested by Allergan.
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