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Harvard s Judy Lieberman Discusses RNAi as a Therapeutic Modality


At A Glance

Name: Judy Lieberman

Position: Professor, Harvard Medical School; Senior investigator, CBR Institute for Biomedical Research

Background: Associate professor, Harvard Medical School — 1998-2004; Assistant professor, Harvard Medical School — 1996-1998; Assistant physician, Tufts-New England Medical Center — 1988-1995; Assistant professor, Tufts University School of Medicine — 1987-1995; Visiting scientist, Center for Cancer Research, MIT — 1987-1989; MD, Harvard Medical School — 1981; PhD, theoretical physics, Rockefeller University — 1974; AB, physics, Harvard University — 1969

After the pioneering work of Rockefeller University’s Thomas Tuschl, Judy Lieberman made RNA interference one of the tools her lab uses to pursue its focus on the antiviral response of viruses, primarily HIV. Recently, she spoke with RNAi News about her work.

How did you get involved with RNAi?

I was intrigued by the Mello and Fire paper [describing dsRNA-mediated gene silencing] — that initially sparked my interest in RNA interference. I actually got involved in it in research when a postdoctoral fellow in Phil Sharp’s lab [at MIT], Carl Novina, came to us when the first rumors of the [Thomas] Tuschl [RNAi] work in mammalian cells were heard. He wanted to know if we could work together to try to see if we could get RNA interference to work against HIV.

What had you been doing up to that point? Was it something that would lend itself to moving into RNAi?

I’m an immunologist, and we study the immunology of HIV. We have a lab that does a lot of work with HIV.

So you weren’t working in gene silencing or anything like that?

Not at all.

Was it a big jump [to RNAi], or has the technology been easy to work with?

In the early days it required some experimental ingenuity to get it to work and to show that it worked. At that time, people didn’t know how to design siRNAs, how to get it into different kinds of cells — it was very early.

The HIV work is still going, correct?

That’s correct.

Where are you at with that?

We figured out that we could silence either host receptors or co-receptors, as well as viral genes, and that we could get silencing to work synergistically and basically completely inhibit HIV replication in an important, relatively drug-resistant reservoir: macrophages. [We also found] that we could down-modulate CCR5, which is important in HIV transmission, for weeks in macrophages. That suggested to me that it might be a good place to try to develop RNAi as a microbicide to prevent the sexual transmission of HIV, and possibly other sexually-transmitted diseases.

That work was done in vitro or in vivo?

There’s no mouse model of HIV, so we’ve done in vivo work in mice to first figure out ways to get silencing in vivo in the vagina of mice. We’ve recently begun testing [siRNAs] in a herpes model of infection and have pretty dramatic preliminary results.

How are things turning out in the herpes model?

We’re getting very good silencing throughout the mucosa, and we’re getting protection preliminarily against a lethal dose of the virus in mice. … [This is] potentially a large market, and it could be used either to prevent transmission or to prevent people from reactivation of herpes, which is a major clinical problem.

During [the Nucleic Acid World Summit in Boston], you mentioned you had managed to deliver to specific cells in vivo. Can you comment on that?

We used HIV as a model. We worked out a method — which we haven’t written up yet, which I’m about to write up — of cell-specific delivery to cells that express HIV envelope on their cell surface, but in principle it could be used for other cells. Basically, we’re able to get transduction or delivery of siRNAs only into cells bearing the envelope. We’ve done it in a variety of model systems, including HIV-infected primary CD4 T-cells, which are virtually impossible to transfect.

We get delivery both in vitro and in vivo only to cells that express HIV envelope. We’ve used it in a mouse tumor model to show that we can inhibit a tumor that expressed the HIV envelope on its cell surface.

Can you talk about how you did this in however specific or general terms as you’re comfortable with?

I don’t want to give you the details, but you can say that its based on a modified antibody fragment to the HIV envelope.

As far as that work is proceeding, what’s the next step?

For HIV, I want to pursue the microbicide first. For that, I think what we’ll have to do is first verify that our preliminary results hold, and then I’d like to go to a primate model where we can challenge primates with SIV, the HIV homolog. Then there’re be questions of formulation, and also of … toxicity, so we have to make sure we’re not causing inflammation locally.

Is this something that you’re doing on your own, or are you looking for collaborators?

I plan to do it with collaborators.

Industry or academic?

For now academic, but I’m looking around for someone to commercialize this.

I’d imagine that once you start getting into primates, things start getting expensive.

Well, there’s a lot of interest in what we’ve done on the part of the NIH, but it’s basically that I don’t want to do all the development work in my lab.

Is that something that’s still preliminary?

I’d say it’s still preliminary. There have been several [companies] that have expressed real interest, but I don’t know where its going to go.

What about with the herpes project?

[Once] we make sure there is no toxicity — inflammation, induction of interferon, inflammatory infiltrates. Assuming that that holds up, then we would have to try to team up with somebody to develop a formulation that we could.

We haven’t optimized anything. There are all sorts of questions. You’d want to figure out the best [formulation], probably a cocktail of viral sequences to use, and optimize that, determine whether chemically modified siRNAs might be better than naked siRNAs.

Has any of the work you’ve been doing looked into the gene therapy type of RNAi?

We have done some work on that. We’ve made lentiviruses that work against HIV, but a number of other groups have, as well.

We’re actually developing lentiviruses for another indication, as well.

What indication?

I don’t think I’m going to tell you.

Is it a viral disease?

No, a genetic disease.

You mentioned looking into a cocktail of siRNAs. Especially with HIV, there’s the issue of escape mutations. Do you anticipate that [cocktails] will be the direction you’ll have to go to develop a viable therapeutic?

I think that you will probably need to have a cocktail to have the best efficacy, and going after a co-receptor like CCR5 with wild-targeting viral genes is a good idea.

My colleague here at the CBR, Premlata Shankar, has identified a sequence that has worked against five different clades of the virus and all the primary viral isolates that we’ve looked at. That would suggest that you may be able to identify sequences that the virus cannot readily mutate against.

Are there any other projects you’ve got going on?

Yeah. We just had a paper in [the Proceedings of the National Academy of Sciences], which is very interesting, I think. [In it, we describe experiments] in which we were able to protect mice from renal ischemia reperfusion injury in the kidney.

Basically, when you cut off the blood supply to an organ, there’s an initial area of infarction where the cells die by necrosis. But when the blood flow comes back, the surrounding tissue dies by apoptosis. Often, the infarction is extended by threefold, so it’s a big extension of the original area of tissue damage.

It turns out that that reperfusion injury is also mediated by fas, and we found that by silencing fas [using siRNAs] we could prevent mice from death from acute tubular necrosis, which is one of the most common causes of death in the intensive care unit of hospitals.

One of the other points of that paper is that we could … just inject the siRNAs into the renal vein, the vein draining the kidney, in a small volume of 100 microliters and get as good protection as we get with hydrodynamic delivery. So this is a method that you could use now clinically, and it suggests the possibility that other organs, like the heart during a heart attack, might be a good target for a therapy.

Is further development something you are pursuing, or is it just a proof of concept?

I’m talking about that with some people.

Academic people?

No, no. Industry people. But it’s still at a very preliminary stage.

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