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The Therapeutic Potential of RNAi

Phil Sharp talks with Technology Review about RNA interference-based therapies on the horizon.
October 2, 2006

One of the biggest scientific advances of the last decade has been RNA interference: a natural process used by organisms from poppies to people to turn off the expression of certain genes. The potential of the discovery was further emphasized by today’s announcement that the Nobel Prize in Physiology or Medicine goes to a pair of American researchers, Andrew Fire and Craig Mello, for their groundbreaking work in RNAi.

While scientists saw the therapeutic potential of RNAi early on, many in the field have remained skeptical that RNAi can be developed into an effective therapy. To date, the technique has been most successful as a scientific tool to study the function of specific genes.

But the tide may be turning, says Phillip Sharp, a MIT professor who won the 1993 Nobel Prize in medicine. Sharp is also cofounder of and scientific advisor to Alnylam, a biopharmaceutical company based in Cambridge, MA, that’s developing RNAi therapeutics. He spoke at the Emerging Technologies Conference on Wednesday, then shared his thoughts on the prospects for RNAi-based therapies with Technology Review.

Technology Review: Where are we in terms of developing RNAi-based therapies?

Phillip Sharp: If you look at the field from a translational point of view, it’s still early. But the technology is clearly advancing, and we may see the first products before a decade. In fact, several early-stage clinical trials are now ongoing. One trial for macular degeneration uses RNAi to try to control vascularization of the retina [growth of new blood vessels that can lead to scarring in macular degeneration –TR]. And Alnylam is in the early stages of a clinical trial testing a treatment for RSV [Respiratory Syncytial Virus]. RSV is a common problem in infants and an untreated issue in older adults that can be life-threatening.

TR: How have these advancements shaped the field?

PS: When we first started Alnylam in 2002, we couldn’t even get the pharmaceutical companies to talk to us. They agreed RNAi was a great lab technique to test for drug targets. But now they’re at the point where they’re thinking this could be a serious treatment modality. I think now, based on the investments they’ve made, they would say it’s very likely that new treatments would evolve from siRNA [short interfering RNAs, one of the molecules involved in RNAi]. The question now is how broad the applications will be.

TR: What are the biggest hurdles in developing RNAi-based therapies?

PS: It’s a delivery issue. If you can get RNA into the cells, then you can see a significant effect. The issue is how do you get water-loving RNA across the water-hating cell membrane? People have used lots of approaches to try to overcome this, such as conjugating an RNA molecule to something else. Nanoparticles, for example, can be constructed to target specific cells.

One important paper, I think, [was] published in Nature this spring by Alnylam. [Researchers put a siRNA molecule that targeted ApoB, a protein involved in cholesterol synthesis, into a specially designed nanoparticle, then injected the particles into a nonhuman primate. –TR] The surprise was that not only did the treatment silence the gene, but the silencing extended beyond 14 days. That longevity is important if you’re going to be able to give someone a treatment once a month. And the treatment worked at a dosage that might be appropriate for a human.

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