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Mount Sinai's Betsy Herold on Using siRNA to Combat HSV Type 2

Name: Betsy Herold
Title: Professor, pediatrics & microbiology/chief, division of pediatric infectious diseases, Mount Sinai School of Medicine, New York, NY
Background: Associate professor, microbiology, Mount Sinai School of Medicine — 2000-2005
Associate professor, pediatrics, Mount Sinai School of Medicine — 1998-2004
Assistant professor, pediatrics & virology, University of Chicago — 1992-1998
Research associate/postdoc, Northwestern University — 1990-1992
Fellow, Children’s Memorial Hospital, Chicago — 1987-1990
MD, University of Pennsylvania Medical School — 1982
BA, biology, Brown University — 1978

At Mount SinaiSchool of Medicine, Betsy Herold investigates herpes simplex virus type 2 to identify the signaling pathways the virus uses to invade cells, and to develop strategies to prevent and treat infection. In recent years, she has incorporated RNAi into her research, both as a tool and as a possible therapeutic agent, including the development of an siRNA-based microbicide for HSV.
This week, RNAi News spoke with Herold about her work.
Let’s start with a bit about your lab and the focus of its research.
Our lab focuses on herpes simplex virus type 2, which is the major cause of sexually transmitted herpes infections. We explore how the virus invades cells, and then try to use that knowledge to develop new strategies to prevent viral infection — in particular, vaginal microbicides.
When did RNAi come into the picture?
About four years ago. To be honest, our studies were not initially thinking about [using RNAi in] microbicides but using it as a tool to unravel the pathway of viral invasion.
Basically, [HSV is] a very complicated virus; it’s got multiple viral glycoproteins on its surface. Most viruses have one or two; HSV has between 11 and 13, depending on which ones you want to be completely sure of. And they’re all involved on some level in either entry or egress or immunization. So it’s been very difficult to understand how the virus really gets into cells.
We started looking at it from the cell’s perspective about 8 or 10 years ago, asking which cellular pathways the virus is usurping or harnessing to get into cells, and siRNAs became a strategy for us to do that. Our initial studies involved using siRNAs to down-modulate things like focal adhesion kinase and other things that are involved in the pathway of viral invasion, and the more we did those studies [the more] it became apparent to us that we could knock down viral co-receptors and receptors on cell surfaces. … So we began asking [if] this could be used as a therapeutic or preventative strategy.
At this point, how old is the RNAi microbicide effort? How long have you been looking to apply RNAi as a therapeutic?
Probably about two or three years.
What sort of targets are you looking at?
I’ve actually talked numerous times with Judy Lieberman [at Harvard’s CBR Institute for Biomedical Research] because she began doing HSV work a little before we did. Our work is similar, but also different in that she’s mostly targeted so far viral targets, and we’re interested in targeting both viral and cellular targets.
The reason for that is when you only [go after] viral targets, you’re targeting the infection after it has occurred. So the virus has to get in, start to make viral proteins, and then your siRNA would block the ability of the virus to express those proteins. The problem with that is we don’t completely understand how the virus establishes latency and how the virus modifies the immune system.
Data from our lab suggests that even having defect viral particles around — viral particles that aren’t even expressing … any viral proteins — may be enough to modify the innate mucosal immune environment. We’d like to get rid of the virus before it has a chance to do anything, so we became interested in trying to target cellular receptors involved in viral entry, but combining that with something targeting a viral protein to hit the virus at multiple steps in its life cycle.
So we’ve been targeting some of the viral receptors, some of the proteoglycans that the virus uses to attach to cells, and some of the co-receptors, as well as targeting some of the viral genes themselves.
It’s interesting you brought up Judy. She’s one of the first people I heard was trying to develop an RNAi microbicide (see RNAi News, 2/6/2004). Are your discussions with her informal, or do you actually have an active collaboration?
Right now my discussions with her are informal. I do collaborate with Bharat Ramratnam at Brown [University], who’s been doing a lot with HIV (see RNAi News, 9/30/2005). Then there are some other people we work with looking at some other viruses.
In terms of approaching the all-important delivery issue, is that the key hurdle at this point?
I don’t think that it necessarily is. There are enough ideas out there [regarding delivery] — and Judy certainly has been taking a lead in that regard — but I think there are still some basic science questions that need to be addressed in terms of what the impact of targeting both cellular and viral genes is. [HSV] is very complicated, and you might target select genes but might end up with over-expression of other viral genes as a response. I think there is still a reasonable amount of work that needs to be done to really understand not only the efficacy but also the safety of this strategy.
I actually think delivery [issues], at least … [when delivering RNAi molecules] locally and mucosally, are not as difficult. Those are much bigger things when you’re trying to deliver systemically or if you’re trying to target specific cells. If you’re trying to deliver something vaginally, you’re kind of targeting the whole area. And it’s a very different population because those are cells that are overturning anyway. That’s a lot easier than saying you’re going to use siRNAs to target cancer cells and you’re going to give [a treatment] systemically.
Have you developed candidate delivery systems at this point?
At this point, we’re just vaginally applying siRNAs in a very simple fashion. We don’t have a delivery system worked out. We’re ironing out the kinks as to what the best system is and we’re also working with different animal models.
Our current interest is to come up with the best cocktails of siRNAs that we think will block infection. We have collaborators I work with in a model of HSV — the cotton rat model. … That animal is unique because [it] gets infection just like humans: If you vaginally apply the virus, it gets infected. But the thing that makes it different from all [other] animal models is that [the virus naturally recurs] just like humans, and you can trigger those recurrences by immune suppressing the animal transiently with a dose of steroids. But it will naturally get infections at about the same rate as humans do, so we also think that that would be a nice model to look at siRNAs as a therapeutic, thinking along the lines of something that would not only block primary infection but recurrences.
Judy and I would love to say that in six months, a year, or two years we’re going to have something ready to go out into phase I clinical trials. But she may be more of a believer in that than I am because I think there is still some legwork to do in terms of trying to optimize what the best targets are, and make sure they really are safe and don’t do other things that we haven’t thought about. Once we’re there, I think delivery will be less of a problem.
Presumably at some point you’d find an industry partner to go forward with this.
Correct. We could use an industry partner for a lot of things we do. [Laughs]
As it stands now in your mind, if you come up with a good siRNA candidate, [would delivery] be something industry would handle?
Yes. There’s clearly more expertise in industry for that kind of work. What we bring to the table from my lab is understanding the viral life cycle and some of the potential candidate targets, and also understanding some of the potential pitfalls of this strategy. This notion that if you turn off one gene other genes might get over-expressed, you have to know the virus to know those things.
Someone else would be a heck of a lot better at formulating and coming up with the best delivery systems and answering those kinds of questions.
Do you anticipate this would be a prophylactic drug or a treatment, or both?
Both. My interest in vaginal microbicides truly has been to prevent women from getting infected by HIV or HSV. I think the HSV story is very complicated because if you go into the developing world, 70 to 80 percent, and even higher in some countries, of young women have already been HSV-exposed. We know that HSV enhances the risk of acquiring HIV for many different reasons that are not completely understood. But if this were to prevent the virus from reactivating, if we could keep the virus down, that might have a secondary positive impact on HIV acquisition.
So I see it as both. But if you’re talking about it from a market [standpoint], certainly people that already have HSV would love you to have something to give to them to prevent recurrences, both sub-clinical and clinical. Sub-clinical recurrences are obviously a concern because you can transmit even when you don’t know you have virus there.
And if you don’t [have an infection], it’s something you could apply prior to intercourse.
You said that maybe certain timelines people have might be a little ambitious. Do you have a sense of when you might have something ready so that you can start thinking about delivery options and moving into humans?
I tend to like the strategy of combination approaches to things and hitting an infection at multiple sites. We’ve already identified a couple of targets where we’ve constructed siRNAs or [identified] siRNAs that already exist, tested them in vitro, shown that they block viral infection by greater than 90 percent, often by two or more logs, and we’ve started to show they’re effective in the mouse model.
Conceivably, we’d be ready to start discussing expanding those studies to the point where you’d have material you could use in a phase I trial. But that’s like coming to the table and saying, “We’ve got the siRNA, here’s our data that shows it works, you guys figure out better how to deliver it and make sure it’s made under cGMP … rules.”
I’m talking a year to say, “These are the two targets you should go after, these are the siRNAs, and we have very good in vitro safety and animal model safety data.” That’s one to two years, and obviously things could go wrong.

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