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December 15, 2004 | Phil Sharp shared the 1993 Nobel Prize in physiology or medicine with Richard J. Roberts for RNA splicing, a seminal discovery that not only transformed scientists’ understanding of gene regulation but also helped give rise to biotechnology. Twenty years ago, Sharp co-founded Biogen (now Biogen Idec). Convinced of the therapeutic potential of RNA interference (RNAi), in 2002 he helped launch Alnylam Pharmaceuticals. From his office at the MIT Center for Cancer Research, Sharp spoke to Nancy Weil.

BITW: Which therapeutic areas do you think have the most promise for RNAi-based treatments?
PS: The most obvious ones are probably viral infections of the liver: hepatitis B and C. Clinical trials are going to begin on macular degeneration. I have a colleague at MIT who has shown that you can inhibit the replication of flu in mice using this technology. That’s a very nice piece of work. And if you think of what you can deliver to the liver, there are metabolic diseases as well that you could potentially have an impact on.

There’s the CNS (central nervous system). The big issue in any drug, but particularly in CNS, is specificity. This technology lends itself to answering that problem because it’s driven by sequence specificity, so I think you could probably anticipate treatment of some CNS situations ... and, hopefully, maybe glioblastoma-type tumors. If we can deliver this to cells circulating in the bloodstream, then I think there are a whole host of leukemias and other diseases — blood cancers — that we know a lot about molecularly (that could be treated with RNAi). We know what genes we would like to inhibit, and that should become possible.

What about the issues of stability and delivery?
That’s where the cutting-edge biotech research is. I’d be pretty confident, given what we now know, that if we can deliver these to all the cells of the liver or all the cells of any organ that we could have a significant therapeutic impact.

The other thing is these are all going to be deliverable by injection. We’re not going to take a pill of RNAi — we’re going to take an injection or an infusion into the bloodstream or into the muscle. Therefore, we need longevity of action that is appropriate for that kind of delivery. So I’d love to get two weeks to a month of circulating a drug to inhibit these processes, or once the drug is in the cell, it persists that long and changes the character of the cell ... Chemical modifications to stabilize the RNAs so they won’t be degraded by blood nucleases or modified by intracellular activities, as well as to promote their uptake, are things that are just cutting-edge research to take this to therapeutics.

Alnylam is a serious company this way, and I think Sirna is also working in this area. Some of the early work was developed by Isis in antisense, which had much the same problems of delivery and stability [as RNAi]. Alnylam and Isis have a [licensing] partnership, so all of that chemistry work is available to Alnylam.

Do you anticipate that some other mechanisms for silencing genes will be discovered?
Yes. We have mechanisms that silence at the level of protein synthesis, RNA stability, and transcription. That’s all three of the major steps. I suspect there will be insights into how those processes occur that will give us indications as to how to take our chemistry, or select sequences, or introduce these things so that they’re more effective.

How will you figure out how the RNAi mechanism actually works?
We know much more than we did three or four months ago. We now know that the Argonaut 2 protein is likely the major nuclease. We’ve got an atomic structure of it, even. We know several other proteins are probably in part of the complex. We know it’s catalytic, and we know how it recognizes, at least in a descriptive way, this small siRNA and picks one strand versus another. All that sort of hurtled forward, and it’s provided a platform of science for us to move forward in drug discovery.

Running Interference 


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