Study on mice suggests flaw in a gene therapy - RNAi

Study on mice suggests flaw in a gene therapy
MAY 26, 2006
By Andrew Pollack
International Herald Tribune
NEW YORK: A large number of mice died unexpectedly in a test of a new technique for inactivating genes that has been widely proclaimed a breakthrough, scientists reported Thursday.

The finding could give rise to new caution about the technique, called RNA interference, which is already widely used in laboratory experiments and is starting to be tested in people as a means of treating diseases by silencing the genes that cause them.

Mark Kay and colleagues at the Stanford University School of Medicine reported Thursday in the journal Nature that the technique, also called RNAi for short, caused liver poisoning and death in mice.

Timothy Nilsen, director of the center for RNA molecular biology at Case Western Reserve University in Cleveland, said: "It's a very striking result - all of the fatalities observed and the toxicity, which was unexpected. It's really a note of concern for rapid therapeutic development of RNAi."

But Phillip Zamore, an RNAi expert at the University of Massachusetts, said the Stanford scientists had used a variation of the technique that was "no longer state of the art" and required a very high dose. The tests already conducted in people involve a different technique and lower doses, said Zamore, who is a co-founder of Alnylam Pharmaceuticals, a company in Cambridge, Massachusetts, that is developing drugs using RNAi.

Kay said he thought the findings were "not a showstopper by any means" for the field. "It's like any drug," he said. "The toxicity depends on the dose."

RNA is the chemical cousin of DNA, which encodes hereditary instructions in genes. RNA was once thought to be a mere messenger in the cell. But in a rush of discoveries over the last few years, scientists have found that RNA plays a more active role in controlling gene activity.

They have found that cells make tiny snippets of RNA, called microRNA, that silence particular genes. And they have learned how to harness that natural mechanism to turn off any gene of their choosing by inserting the proper piece of RNA into cells.

But Kay said his experiment showed that if too much interfering RNA was put into a cell, it could overtax the cell's ability to process its own microRNA.