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Dmitry Samarsky On Sequitur s Stealth RNAi and the Delivery Hurdle

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After originally joining closely held RNAi firm Sequitur as a research scientist, Dmitry Samarsky quickly became more and more involved in the company’s business operations. Now Sequitur’s director of technology development, he recently spoke with RNAi News about the firm and its goals for developing RNAi-based therapeutics.

How did you get started in RNAi?

Organically with [Sequitur] … When I joined the company we were mostly doing antisense. And then, when we were evaluating and switching to RNAi technology, that’s exactly what happened with me, as well. I was one of the promoters of RNAi technology here at the company and really tried to move it forward as quickly as possible.

Sequitur’s RNAi technology uses RNA strands slightly longer than the 21 to 25 base pair strands commonly used by others, is that correct?

We sell regular siRNAs and we also have our proprietary technology, which we call Stealth RNAi technology. The purpose of this technology is to get rid of potential interferon responses. So, these are chemical modifications of duplexes, which result in abolishing the interferon response and … make those compounds more resistant to nucleases.

The size doesn’t matter. When we were doing our initial experiments, we identified siRNAs which stimulate PKR and interferon responses, and we were making chemical modifications in those regular siRNA compounds … so they wouldn’t stimulate the interferon response. That also opens the door for different lengths.

So, in principle, Stealth can be applied to any length of double-stranded RNA … Our standard Stealth RNAi at this point, the one that we sell … they are usually 27-mer.

Can you describe further what these Stealth RNAi compounds are like structurally?

That’s a very tricky question. We filed a [patent] application on that. And we may have something published [in a peer-reviewed journal], which would describe our first steps in Stealth technology. But the exact modifications and how we’ve done those, at this point, are proprietary information.

You are using Stealth RNAi with your research product offerings and with your RNAi-based drug candidates?

Yeah. When we were developing our Stealth RNAi, we were sort of shooting in two directions. One is to make it non-toxic or non-stimulatory to the interferon machinery. The other one [was] to make it stable in serum; stability in serum is certainly an important issue for development of therapeutics [in addition to] specificity.

We [also] realized that, after we developed these compounds, that they … are potentially a very good tool for target validation, for regular gene function analysis in vitro, as well.

In terms of RNAi-based drug development, can you describe the efforts that are going on at Sequitur?

Historically, the antisense technology is sort of a proven technology as a potential drug modality … because there are drugs on the market and there are a lot in clinical trials. So, a lot of things have been done, a lot of mistakes have been done, and a lot of lessons have been learned.

The way we approach this problem, rather than start from the target like the way it used to be done initially with antisense … [is] to find out where we can deliver the RNAi compound. And then, based on the organ where we can deliver the RNAi compound, we will identify the diseases associated with those organs.

For example, if we can deliver it to the liver, we would associate it with diseases like cirrhosis … If we managed to deliver it into the lungs, we would probably try to treat asthmas and COPD and RSV, for example …

The most promising directions are the liver, the lung, and we have some data with our Stealth RNAi compounds in tumors … with our partner Intradigm. We have an agreement, signed with them some time ago, where we … give them certain access to our Stealth technology. In exchange, they give us certain access to their in vivo delivery technology ...

We are [also] looking right now at having more partnerships with pharmas in order to [develop therapeutics]. At this point, we mostly provide lead compounds and then we would need to do partnerships for the later stages of drug development … [We would also] license out [compounds] for big pharma to develop on their own.

Can you comment at all on Sequitur’s delivery approaches?

[The tumor experiments involved] direct delivery with specifically formulated compounds. This is not a naked compound … [But] now have modifications that stabilize the RNAi compound, [which] opens the door for actually using the naked RNAi, and that’s something we want to do. We want to find out if a naked RNAi compound could go into certain organs by itself … Non-viral delivery, just chemically modified compounds injected [intravenously or intraperitoneally].

With the lung project, how is the RNAi compound delivered? Is it inhalable?

That’s something we would want to have… just by inhalation. That’s the easiest way and probably the most direct, certainly.

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