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Dharmacon s Stephen Scaringe on the Present and Future of siRNA

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At A Glance

Name: Stephen Scaringe

Age: 39

Co-Chairman and CSO, Dharmacon

Background: PhD, chemistry and molecular biology, University of Colorado at Boulder — 1995 Researcher, MIT — 1987-1990 Teaching degree, secondary education, Wellesley College — 1989 BS, chemistry and biology, MIT — 1987

Scaringe co-founded Dharmacon in 1995 while he was still a graduate student at the University of Colorado at Boulder. Since that time, the company has expanded into siRNAs and experiment kits, including SmartPool — a set of four or more siRNAs the company guarantees will yield at least a 70 percent knockdown 99.9 percent of the time.

Scaringe recently sat down with RNAi News to talk about the company and how it is approaching the RNAi field.

How did you get involved in RNAi?

Dharmacon got involved in RNAi in 2001 as [the technology] was emerging and gaining recognition. As the leader in RNA synthesis, which is one of the enabling technologies for RNAi … the customers turned to Dharmacon as this technology was emerging, looking for us to bring advances and deliver what they need for the field.

It stems from the close collaborative relationships Dharmacon has with people working with RNA in the field. So right from the beginning, we had discussions with people like Tom Tuschl, Phil Sharp, Phil Zamore, Dave Bartel, and others, about what Dharmacon can do to help with the emergence of the RNAi market.

Could you give a general overview of Dharmacon’s business operations?

Sure. The business model is integrating chemistry R&D, biology R&D, bioinformatics, RNA production, integrating all those resources and capabilities to drive innovation in RNA-dependent applications. So, because we are a leader in RNA synthesis technologies, providing RNA oligos to a broad range of people with a very diverse range of applications, as RNA-dependent applications emerge, by having all these capabilities … we are able to work with the emerging market to help develop the application for new technologies.

How much of your business is siRNAs?

[I] wouldn’t be able to give an estimate on that. … It’s a significant portion of our business.

More than half?

More than half would be safe. Yes.

Can you comment on the revenues Dharmacon generates annually?

As a private company, I wouldn’t be able to comment on numbers.

Is the company profitable?

Yes. That’s been another key component of Dharmacon and our business model … to focus on being a successful business so we can continue to bring advances … to customers and the market. We started producing revenue less than a year into starting the company, and from the second year on we’ve been profitable and growing revenues [with] an annual growth rate of over 100 percent. … So we’ve essentially been doubling revenues on an average basis for the past six, seven years. At the same time, we’ve been profitable every year.

One of the approaches Dharmacon takes to deal with off-target effects involves sense-strand modifications. Can you comment on that?

I think, perhaps, the most overriding factor, really, for Dharmacon is what I call close collaborative relationships with customers … working closely with customers at the cutting edge. So, for example, [with] off-target effects, our relationship with Rosetta. This is something that has evolved over the past year and a half, and by working with customers, and by having in-house expertise, we both made discoveries both in- house, as well as via our relationships with customers, of issues that are arising for the customers, off-target effects being one of those.

We started seeing those in-house, and by working with Rosetta, we were privy to their observations and discoveries.

[Rosetta vice president of research] Peter Linsley mentioned [at the New York Academy of Sciences RNAi symposia on Oct. 27] that these sense-strand modifications seem to change the off-target effects, but do not eliminate them. Is that correct?

Off-target effects is a very broad term and there can be 20, 25 different causes for off-target effects, of which homology to the sense strand seems to be one notable source, at this time. Modifications to the sense strand help to mitigate off-target effects stemming directly, perhaps solely, from homology to the sense stand. You also had a chance to hear Phil Sharp speak [at the symposia] on translational arrest and the overlap between the microRNA pathway and the siRNA pathway, and that perhaps some siRNAs, [where there] is not perfect homology, may play a role in translational arrest. That may be another off-target effect. It’s too early to tell.

What about the algorithms for your siRNAs?

It’s definitely … something that will continue to evolve. The current version that we utilize commercially focuses on eliminating poorly functioning siRNAs, ensuring that most if not all of the siRNAs have a 70 percent knockdown or higher. Internally, further refinements of that, and building on that version, include incorporating algorithms to address off-target effects and specificity, [and] BLAST algorithms to better use mismatch information. For example, we’ve given recent presentations where it’s not enough just to have two or three mismatches, but where mismatches are can be important. …

Also hyperfunctional siRNAs. … We’re the first to really identify that there’s some siRNAs out there that that last a relatively long time. … This is something we’ve been noticing for the past year. So, further refinement is, “Can we have a selection algorithm to not only find functional siRNAs, eliminating poorer function ones, but also identify hyperfunctional ones?”

Does Dharmacon plan to remain offering its services and providing oligos, or do you plan to expand into other areas?

Referring back to our business model, it’s really to provide know-how and expertise in enabling a customer or researcher. Because of our leadership in RNA synthesis, people look to Dharmacon to provide leadership in an emerging technology that was in part enabled by RNA synthesis. …

I expect to see this as a constant evolution where RNAi, itself, will also lead to new advances and technologies … and subsequently our customers may look to Dharmacon to help where RNAi leads them.

At the same time, in parallel, you can go to so many conferences and [see] the excitement about RNAi, or just RNA, in general. As was mentioned [at the NYAS RNAi symposium] one to three percent of the human genome is expressed. What’s the rest of it? Is it non-coding RNAs? There’s so much to discover out there about RNA. We foresee a number of other RNA applications emerging. Likewise, in RNAi ... it will … lead to other technologies Dharmacon can play a leadership role in.

Where do you see RNAi going?

[C]learly in functional genomics, in terms of really identifying roles for genes — how different genes interact. It will really give us a bigger picture of all the activities in the cell. That’s one example.

Another may be RNAi therapeutics. In that case, using our know-how and discoveries to assist those that want to be developing siRNA as a therapeutic.

How realistic an idea do you think RNAi as therapeutic is?

That’s a good question. There are a number of companies out there that see a potential for siRNA as a therapeutic, and have the expertise to deal with all the issues involved. It’s complex, involves a number of different disciplines to … realize siRNA as a therapeutic. Dharmacon is playing a role to share our expertise, our know-how, and discoveries with those people as they work towards trying to develop siRNAs as therapeutics.

But how viable do you think the technology is for therapeutics … in your personal opinion?

Gosh, that’s a hard one. I think there are a lot of people who believe that there’s a lot of promise and hope there. And, there’s a lot we can do to help them. … I respect a lot of the people who are pursuing siRNAs as a potential therapeutic.

Is there anything else about the company that you want to touch on?

I think the one common theme is that you’re going to continue to see more … close collaborative relationships, really helping to make discoveries that are going to enable RNAi to be a mature, well-developed tool and technology.

When’s the IPO?

Some ways [away], [but] we’ve got a very strong track record and strong future ahead of us. ...

We’ll keep you posted.

 

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