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Free University Berlin s Jens Kurreck on Researching and Applying RNAi

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At A Glance

Name: Jens Kurreck

Position: Assistant professor, Free University Berlin

Background: Postdoc, Free University Berlin — 1999-2001; Postdoc, Arizona State University — 1998-1999; PhD, biochemistry, Technical University Berlin — 1998; Masters, philosophy, Free University Berlin — 1994; Diploma, biochemistry, Free University Berlin — 1994

Although he maintains an interest in philosophy, occasionally publishing work in the field of biomedical ethics, Jens Kurreck has dedicated himself to molecular medicine, focusing largely on gene-silencing technologies such as RNAi and antisense. Recently, he spoke to RNAi News about his work.

How did you get involved with RNAi?

We started a project in the area of pain research together with a German company called Grunenthal, and we did the target validation part. When we started in 1999, it was not the age of RNAi, so we started with regular antisense oligonucleotides and ribozymes.

In 2001, when RNAi became famous [for working in] mammalian systems, we immediately switched to this field.

Are you still working with antisense and ribozymes?

I still use all three because I regard these not as competing methods but as complementary methods. For example, everybody is aware of these warnings that have been reported on RNAi about unspecific effects, off-target effects, or interferon responses. If you have a completely different method, like classical antisense oligonucleotides, you have an independent approach to verify your results. So we still use all three.

We started with antisense and already had our first results. For example, from this collaboration with these pain researchers we had some results with antisense. We then had the siRNAs and confirmed the antisense in vivo results with the siRNA.

Given that you’ve worked with the three technologies, can you talk about the benefits and downsides of each of them?

In our hands, RNAi is the most efficient method. We have nice results with ribozymes, actually deoxyribozymes made of DNA in vitro, but we don’t have efficient cell-culture effects, so they’re a bit behind the other techniques.

We also have very nice antisense experiments when we apply newly developed modified nucleotides. For example, we have locked nucleic acids — it’s a rather new modification. These are much better than the conventional phosphorothioates. They are much more efficient — you need much lower doses for locked nucleic acids than for phosphorothioates. They are close to the range of [efficiency] siRNAs, but usually siRNAs are more efficient.

What sort of projects are you doing now with RNAi?

Our new main focus is antiviral research. We’re involved in a new project which deals with the Coxsackie virus and that causes heart infections, which are very often lethal. We’re currently developing siRNAs against this Coxsackie virus. One of our latest things is to generate a double-expression vector, which expresses two siRNAs at the same time — something like a combination therapy, which might help in the long run to prevent escape mutants that arise when siRNAs are used against viruses.

Is this a target-validation project, or are you looking into RNAi-based treatments against the virus?

Actually, we have collaborators from a clinic and they are developing vectors for gene therapy. So the goal is to go into the animal model to prevent viral infections. In the long run, it would be our goal to go into clinical trials, but that is not within the next [few] years.

What are some of the biggest hurdles you need to overcome to get this into the clinic? Is it still mainly a delivery issue?

First of all, the delivery issue is probably the most important problem for RNAi and all these oligonucleotides. In addition, we do not really understand RNAi completely, so we’re not so sure about adverse effects. Personally, I would like to [see] more research in this area before I would dare to go into the clinic.

What about other RNAi projects?

We still continue our pain project. The pharmaceutical company we’re working with is looking for new strategies to treat chronic pain, because the medication is still pretty bad in this area — either it doesn’t help or there are severe side effects.

Our basic target is the vanilloid receptor, which is a very hot target in pain research. Together with this company, we optimized siRNAs and antisense molecules in cell culture, and they used them in animal models and reduced pain sensitivity of animals in various pain models.

RNAi was much more efficient.

Where does this project stand? They’ve done animal testing, is that still ongoing?

It’s ongoing, yes.

Is there anything else that you’re working on with RNAi?

We had a project — I don’t know if we will continue it — on angiogenesis. We had two closely related isoforms of the so-called hypoxia-inducible factor, which is an important regulator in angiogenesis. Here we had the advantage of a small pharmacological tool — you probably would not be able to block either of these isoforms, but with these siRNAs, you can separately block one of the isoforms. We investigated their functional roles — they are called hypoxia-inducible factor 1-alpha and 2-alpha.

That was just published recently in FASEB. Actually, our collaborators are the main authors, but we brought the whole RNA interference technique into the project.

Is that a lot of the work you do? It sounds like a lot of groups are turning to you guys to help them out with the RNAi side of things?

My business is two [things]. First of all, I look for these collaborations, researchers who are not familiar with these knockdown techniques, and I bring the technique. On the other hand, I try to improve the technique itself. For example, in the antisense field with the design of these locked nucleic acid antisense molecules, or to generate these double-expression vectors.

We also have ongoing much more basic research on what is important for the efficiency of siRNAs: Is it the siRNA sequence itself or is it the target structure? Most people nowadays say it’s just the siRNA sequence itself — you know these [Anastasia] Khvorova papers from Dharmacon.

But [working with] stable hairpins or highly accessible target regions … we have found a nice linear correlation between siRNA activity and accessibility of nucleotides.

So that is what we work on: the technique itself or we use [RNAi] with collaborators on medical projects.