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Protiva s MacLachlan and USAMRIID s Geisbert on SNALPS, siRNAs, and Ebola

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Name: Thomas Geisbert

Position: Research microbiologist/chief of viral pathology and ultrastructure, United States Army Medical Research Institute of Infectious Diseases

Background: PhD, molecular pathobiology, Uniformed Services University of the Health Sciences

MS, biology, Hood College Graduate School

BA, biology, Western Maryland College

Thomas Geisbert
Research microbiologist/chief
of viral pathology
and ultrastructure
United States Army

Name: Ian MacLachlan

Position: CSO, Protiva Biotherapeutics

Background: Research scientist, Inex Pharmaceuticals -- 1996-2000

Postdoc, University of Michigan -- 1994-1996

PhD, biochemistry, University of Alberta -- 1994

BSc, biochemistry, University of Alberta -- 1988

Ian MacLachlan
CSO
Protiva Biotherapeutics

Despite being embroiled in a legal battle for control of its key delivery technology (see RNAi News, 5/4/2006), Protiva Biotherapeutics, along with collaborators at the United States Army Medical Research Institute of Infectious Diseases, last week published in the online versions of the Journal of Infectious Diseases a paper describing the post-exposure protection of guinea pigs from a lethal dose of Ebola virus using siRNAs delivered with the company's SNALP technology.

This week, Thomas Geisbert, a USAMRIID researcher and co-author of the paper, and Protiva CSO Ian MacLachlan spoke with RNAi News about the research.

Let's start with the SNALP technology. Could you give an overview?

MacLachlan: SNALP stands for stable nucleic acid lipid particles, and these particles are a delivery system Protiva has developed for the delivery of nucleic acid-based drugs. The key point [is] the full encapsulation of the nucleic acid payload, which pharmaceutically enables it so it behaves like a drug. We've applied this technology now to the delivery of siRNAs and the [Journal of Infectious Diseases] article is the third significant report in which our technology has been enabling for siRNAs.

The first report [detailed] SNALP-mediated inhibition of hepatitis B viral replication in mice. We published this work in Nature Biotechnology with … Sirna [Therapeutics], and this was the first example of antiviral activity using a clinically viable systemic dosing regime [of siRNAs] (see RNAi News, 7/29/2005).

The second report we published earlier this year [described] SNALP-mediated apoB knockdown in non-human primates (see RNAi News, 3/30/2006). This was published in Nature with … Alnylam [Pharmaceuticals], and this was the first example of systemic RNAi in primates. It was probably the first study in primates that convincingly demonstrates an RNAi-mediated [therapeutic] effect of any kind.

This third report [describes] the post-exposure protection of Ebola-infected guinea pigs [and] is being published in the Journal of Infectious Diseases with … USAMRIID. This a very rigorous test of SNALPs antiviral activity, which I would suggest we passed with flying colors.

Could you talk about how the research was structured?

MacLachlan: The study was initiated when I approached Tom Geisbert at USAMRIID as being the real leader in the Ebola field and explained to him what we wanted to do, which was to apply SNALP technology to the delivery of siRNAs to treat Ebola viral infection. It turns out that Tom … and his colleagues were already working on siRNAs but were having a hard time applying what they learned in vitro to the treatment of infected animals in vivo. So we took siRNAs directed against the L polymerase of Ebola, which is an RNA-dependent RNA polymerase that is a necessary component of Ebola replication. We encapsulated these siRNAs in SNALPs, and then used … [them] either as a pool of four active molecules or individually, and treated Ebola virus-infected guinea pigs.

What we found was that there was a profound impact on the survival of the infected animals, and that this correlated with a profound impact on the Ebola viremia in those same animals. We were able to confer complete protection with either a pool of siRNAs encapsulated in SNALPs or individual SNALP siRNAs, depending on their relative potency.

So the pooled siRNAs didn't necessarily work better than one of the four on its own?

MacLachlan: The most potent siRNA, which we refer to as EK1, was essentially equally potent to the pool in that it conferred absolute protection, that is 100 percent survival, and also contributed to complete aviremia in the infected guinea pigs. So there was no detectable Ebolva virus even though the animals had been inoculated with essentially 30,000 times the lethal infectious dose for the virus.

Can you talk a bit about Ebola and why USAMRIID feels it makes a good target for RNAi intervention?

Geisbert: Our mission at USAMRIID is to develop countermeasures to protect the war fighter. It's pretty well known that the former Soviet Union was developing Ebola and Marburg viruses for potential use for biowarfare. That's why we're looking at [the virus]. As far as the technology goes, we're certainly interested in post-exposure treatment modalities for these viruses, and RNAi certainly looked like it had some utility for this. Of course, [Ebola] is an … RNA-dependent RNA polymerase virus … [so] it's pretty much an ideal target to go after [with RNAi].

Is this work part of the collaboration USAMRIID has with Alnylam (see RNAi News, 4/13/2006)?

Geisbert: [No,] that's not the work I'm doing.

What's the next step with these data in hand as far as moving this forward?

Geisbert: We use the rodent models to … see if something is worth taking into a non-human primate, because there are ethical and cost issues -- monkeys cost us anywhere from $5,000 to $6,000 a piece, in addition to the ethical issues. Ideally, you want to show that whatever your strategy is, that it can completely protect rodents from disease. Then you'd have some reason to test that strategy in a non-human primate.

So there is more rodent work to be done?

Geisbert: Sure. These results are highly encouraging, and I think from our perspective the most encouraging part is that not only did the guinea pigs not die, but they didn't get viremic. That's pretty important. My experience with these viruses has been that if you can't really protect guinea pigs from getting viremic then your odds at protecting monkeys are not as good. So if you can at least completely protect the guinea pigs then you have at least some chance of transitioning [a treatment] to non-human primates.

MacLachlan: Isn't it correct that this is the first therapeutic approach in which you've been able to completely protect guinea pigs from viremia?

Geisbert: We had one other one in which we used a recombinant antibody where we were able to completely protect [the animals], but the doses were pretty high to the point where they might not be too good for the monkey.

What sort of doses were used in this study?

MacLachlan: The siRNA doses were .75 milligrams per kilogram. The dosing was initiated one hour after inoculation with the virus, and then repeated every day thereafter for a period of six days.

Assuming that all additional studies go well, what sort of timeframe would you be looking at for the development of this drug?

Geisbert: We're targeting the L polymerase, [but] that is one target. Before we went into monkeys we'd probably want to look at multiple targets. [We'd] then pick what we feel are our strongest siRNAs and try a pooled approach in non-human primates. If you're talking about how long this would be for humans, we're talking quite some time.

MacLachlan: Protiva is certainly interested in the public health and commercial opportunities that arise out of this work, but we also have to be careful to evaluate it within the context of our other product-development programs. However, the results are really quite compelling and we look forward to supporting the preclinical work as we move from these guinea pigs into the non-human primate studies.

Geisbert: I would say, realistically, within the next year we would want to start doing the non-human primate studies for Ebola.

Does Protiva and USAMRIID have any sort of official relationship to develop this [Ebola drug]?

MacLachlan: We're operating within the terms of a cooperative research and development agreement.

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