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USAMRIID s Sina Bavari Discusses Collaborating with Alnylam on Biodefense

Sina Bavari
chief of immunology, target identification, and translational research
United States Army Medical Research Institute of Infectious Diseases

Name: Sina Bavari — chief of immunology, target identification, and translational research, United States Army Medical Research Institute of Infectious Diseases

Background: Postdoc, National Research Council — 1991-1994

PhD, pharmaceutical science, University of Nebraska Medical Center — 1991

Nuclear PharmD, University of Southern California — 1983

PharmD, Creighton University — 1982

Last week, Alnylam Pharmaceuticals announced that it had signed a cooperative research and development agreement with the United States Army Medical Research Institute of Infectious Diseases to collaborate on the discovery of RNAi-based drugs for biodefense (see RNAi News, 4/13/2006).

Under the CRADA, Alnylam will work with the USAMRIID to discover RNAi agents targeting viral organisms that have the potential for use in biowarfare, namely hemorrhagic fever viruses.

This week, Sina Bavari, who is heading up the collaboration for the USAMRIID, spoke with RNAi News about the effort.

Let's start with an overview of your lab there.

Our lab is mainly focused on finding vaccines and therapeutics against biodefense agents, and understanding the mechanisms of microbial evasion from innate and adaptive immune response. It's really broad.

These biodefense agents, do they run the spectrum or is there a focus?

My lab doesn't have a specific focus on any biodefense [agent]. We work on Ebola, Marburg, some of the bacterial agents like Francisella tularensis, Bacillus anthracis, [and] Burkholderia mallei. On the toxin side, we work on finding therapeutics, especially small-molecule therapeutics, for botulinum neurotoxins and Staphylococcal enterotoxin B.

Is there any one that's a real priority at this point?

I think botulinum neurotoxins would be the highest priority.

So this collaboration with Alnylam, is this the first time you are getting involved with RNA interference?

We had some initial data suggesting that RNAi might be a good mechanism to inhibit viral replication, especially for Ebola and Marburg. We have some preliminary in vitro data suggesting that, and then … we started talking [to Alnylam] about possible targets [and] possible strategies to go about hitting these targets with RNAi.

We really needed to have a collaborative effort with a company that knows how to make RNAi [agents]. The problem is targeting the correct site, and we don't have that kind of capability.

What will be your first [goal] under this collaboration?

I think the first [goal] will be to try to inhibit the replication cycle and the replication machinery of the Ebola and Marburg viruses.

Can you give a breakdown of how the collaboration is working — who's doing what?

The idea would be that we'd provide them with the targets to go after. They would be preparing the RNAi [agents] that hit the target and probably some other ones around it with various proprietary [technologies] they have to facilitate entry into the site of action.

Do they then give you the [agents] for testing?

That's correct.

How does the testing process work?

We've done some in vivo work and its shown great promise. The idea would be that you'd get some hits, hopefully, from looking at these in vitro in cells. Maybe even prior to that you'd look at them in some sort of replication machinery … and then move that into cell lines. From there, you'd move into target cells like dendritic cells, monocytes, and macrophages of human origin. We'd move these into a mouse model for Ebola or a guinea pig model for Marburg, and if things are working out, you slowly move up into a non-human primate model.

What do you anticipate the timeline on this sort of research would be?

I'm hoping, and it depends on funding and our capacity here, in a year we should have things working in primates. I'm being optimistic.

Is there a different sort of regulatory path you would follow because these are biodefense agents?

There's no real way to test these in [clinical] efficacy models except in areas where you get sporadic outbreaks. That's one way you can do some very small efficacy testing, but beyond that we use animal models as a way to determine if a compound is efficacious or not. Then you have to set up some correlation between animals and humans.

[Any] phase I clinical trial is a typical study — you just have to make sure things are not toxic. Then you can do expanded phase I trials. It would be difficult to do phase III and IV with these in humans.

Have you had experience with the FDA in trying to get approval for drugs for these kinds of conditions?

We haven't been directly involved, but another company I deal with has been. The regulatory path seems to be not as straightforward as the conventional path, but that could be good also.

So maybe you could get some sort of limited approval?

That's correct.

Has work started under the collaboration?

Yes. And again, the collaboration has started with using some of [Alnylam's] compounds in vitro in cells.

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