Recent biomedical history doesn’t help settle the uncertainty. In fact, this isn’t the first time scientists have tried to make a drug based on silencing RNA. Single-stranded “antisense” RNA or DNA can also shut down genes-and doesn’t need a vector. Inside the cell, an antisense molecule finds its complementary messenger RNA and, like two sides of a zipper, they bind tightly, preventing the messenger RNA from going through the protein-making machinery of the cell. The result, in theory at least, is gene shutdown.
Antisense, though, has so far been a disappointment as the basis for new drugs. After more than a decade of intense developmental work, only one antisense drug-Isis Pharmaceuticals’ Vitravene, for the treatment of certain rare eye infections in AIDS patients-has won Food and Drug Administration approval. The first generation of antisense drugs, which were tested in the early 1990s, rapidly degraded in the body, were hard to get into cells, often failed to find their target, and caused severe side effects. More stable antisense drugs are now being tested in humans.
Can RNAi do better than antisense? Not anytime soon, predicts Frank Bennett, vice president for antisense research at Isis. “If you compare RNAi to the current version of antisense, there really is no advantage,” he says. “[Small interfering] RNA technology is really in its infancy. It’s somewhat equivalent to where antisense was 10 years ago, when we were just beginning to do experiments in animals.”
But RNAi people see their technology as fundamentally different from antisense. “The big advantage here of RNAi over antisense is that, lo and behold, this actually really works,” says Cenix CEO Echeverri. RNAi, he says, is far more potent and reliable than antisense. “Antisense projects were typically seen as suicide projects,” he says. “You could spend a lot of time getting it to work, and it would never work. You’d be left with nothing to show.” RNAi’s greater potency, Echeverri believes, should yield better therapies. And because less drug will be needed to silence a gene, there should be fewer side effects.
People have been struggling with antisense, and here’s a technology that comes along that really works,” agrees Jon Wolff, chief scientific officer of Mirus, an RNA therapeutics company in Madison, WI. “Antisense is hard to reproduce, but RNAi is something that works right out of the barrel.”
But could RNAi be just another overhyped technology? “The proof is in the pudding,” says Echeverri. “Over the last two, three years, RNAi has just completely taken over. Everyone is turning to it; in every organism they’re trying it. And it wouldn’t be this popular if it weren’t successful.”