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Iowa s Beverly Davidson, on Aiming siRNA at Neurogenetic Diseases


At A Glance

Name: Beverly Davidson

Position: Professor, University of Iowa

Background: Associate professor, University of Iowa — 1998-2001; Assistant professor, University of Iowa — 1994-1998; Assistant professor, University of Michigan — 1994; Fellow, University of Michigan – 1990-1992; PhD, biological chemistry, University of Michigan — 1987; BS, biology/chemistry, Nebraska Wesleyan University — 1981

As RNA interference potential in mammals came to the forefront several years ago, Beverly Davidson began combining the technology with her own interest in neurogenetic diseases with the hopes that it would overcome the failures she experienced with antisense and ribozymes.

Recently, Davidson spoke to RNAi News about her work and where it’s headed.

How did you get started with RNAi?

I’ve been interested in neurogenetic diseases since my graduate career — I started out on Lesch-Nyhan syndrome and was interested in the pathophysiology of that disorder and trying to figure out ways for gene replacement.

I moved from that into other monogenic disorders where gene replacement would appear to have a beneficial effect on the disease progression in children affected by mutations in these genes. I’ve thought a lot about how we could go about targeting dominant neurogenetic diseases, but there really haven’t been the tools available; in the past there’s been antisense, and I’ve played with that at the bench, and ribozymes, and I’ve played with that at the bench, but I was never really satisfied with their efficiency.

So, when I read some of the early papers in the late 90s on RNAi in worms, we developed hypotheses that we could put these things into viral vectors and accomplish silencing in mammalian cells. We tried for several years to get effective silencing in mammalian cells, to no avail. Then, when we switched to the short hairpin approach, things just took off.

When you were working with antisense and ribozymes, what was it about those technologies that you felt was less than ideal?

It was variable responses. It probably also re-flected a little bit of my naiveté at the time when I was trying those technologies. In our hands, in my hands particularly, they weren’t as straightforward as the short hairpin-mediated silencing approach turned out to be.

Where does that bring us to now? Can you touch on your work in the area?

I’ve been working on viral delivery to the CNS for about the last 12 years, and it was just a perfect marriage of taking advantage of what I have learned [about] how to deliver genetic material into the central nervous system with what we’ve [and others have] developed in terms of short hairpin-mediated silencing of gene expression to move toward dominant neurogenetic diseases.

In terms of specific projects, can you talk about that?

We’re focused right now in my laboratory, in terms of the RNAi-based approaches, on dominant neurogenetic diseases that are due to polyglutamine repeat expansion. These studies are in collaboration with Hank Paulson at the University of Iowa, who’s a MD/PhD neurologist. Our work on one of these disorders, spinocerebellar ataxia type 1, is also in collaboration with Harry Orr at the University of Minnesota, who developed the mouse model that we use to test our hypotheses.

Where are you with these two projects?

The spinocerebellar ataxia project was just presented at the recent ASGT meetings in Minneapolis, where we’ve shown an astounding level of efficacy with RNAi delivered by viral vectors to the model that Harry developed. That’s work that I can’t go into in too much detail [on] — it’s in press in Nature Medicine.

The other polyglutamine repeat disorder that we’re focusing on is Huntington’s disease. The work is very promising — it’s coming up right behind the spinocerebellar ataxia work.

These are all in mouse models.

I’d imagine that a lot of the difficulties that one would expect to encounter, transforming this from something in mouse models to something in humans … are on the delivery side.

I think that’s very fair to say — that delivery is a major issue. That’s why I think we’re so well poised here, because the viral vectors that we’re using have been used in larger animal models and used in large mammals, and [have been] shown to be capable of delivering genetic material to our target cells [and to a significant proportion] of our target cells.

I think that the beauty of it is that the RNA interference is working and the viral delivery side of things is also looking quite promising. If we can marry those two things, it will be exciting.

Can you talk a little about the vector systems you use?

Yes. Because these are chronic disorders, we’ve taken the approach that we’ll need fairly long-term silencing. When I say silencing, I mean partial knockdown of gene expression — this is not a knockout; we’re not inhibiting gene expression 100 percent. We think that 50-60 percent knockdown of expression is going to go a long way to ameliorate the phenotypes.

What we’ve focused on are two vector systems that [have] shown to confer long-term delivery in [the] brain. One is adeno-associated virus and the other is lentivirus-based vectors. We’re working with both vector systems because we’re not clear, at this stage, which one is better.

Fifty to 60 percent knockdown is sufficient?

That’s at the protein level. We see efficacy with that much knockdown. At the RNA level it’s more on the order of probably 80 percent knockdown.

So, you find your work with these delivery systems encouraging, but there must still be some issues that remain. Can you talk about hurdles that have yet to be overcome?

I think some of the issues that remain, from my perspective, are the specificity of the silencing, and that’s something that we’re working in collaboration with others to try and assess. Are there untoward effects from the RNAi in the central nervous system? The last thing that we’d want to do is induce more disease than is already there. Thus far, the data in animal models is encouraging: When we introduce RNAi into a wild-type brain, we’re not seeing any apparent deficits that would be induced by that RNAi, in terms of cell loss or neurodegeneration or an induction of behavioral deficits where none existed before.

So, at a global level it appears very promising. I’m sure if we look at the molecular level there’ll be some changes and at that point we’ll have to assess: What are these risks and do they preclude any beneficial effects of the RNAi?

But that’s more of an issue with how an RNAi molecule is designed?

Yeah. I think you can play with the design. There’s been some very nice papers from other groups that have shown that if you play with the sequences a little bit you may improve the specificity of the silencing.

We developed all of our systems before those rules, as it were, came out. So, I think that we could certainly refine the sequences that we’re using if it turned out to be a problem.

Other issues you’re facing?

I think one other hurdle is actually a biological question that is quite interesting. We know, for example with Huntington’s disease, the protein … that is mutated in the disease is quite important in neural development. What is unknown at this time is what happens if we partially reduce expression of that protein in an adult neuron. Would that be deleterious or not?

If it is deleterious, if we knock down both the mutant allele and the wild-type allele to, say, 60 percent, and the phenotype improves but the neuron doesn’t like it, then we’ll have to develop ways to silence only the disease allele. We’ve had success with that — this is through my collaboration [spearheaded by] Hank Paulson here at Iowa. We’ve had success developing allele-specific RNAi for several neurogenetic diseases. We would envision the ability to translate that to something as important as Huntington’s disease, as well.

What does it take to do allele-specific RNAi?

The way we would envision this happening for Huntington’s disease is that we’d hope to find a disease-linked polymorphism, a single nucleotide polymorphism, within the Huntington gene itself, which is in the transcribed messenger RNA — some flag if you will, some difference between individuals that have a mutant Huntington allele versus those non-mutant Huntington alleles, some flag that we could target with the RNAi. It’s generally a small sequence polymorphism.

In terms of longer-range plans for you, are there any areas you might like to extend into?

That’s a big question. I’m very focused on doing what I can to translate this forward from mice to therapy. Right now, I’m very focused on that particular aspect.

I also have an MD/PhD fellow in the lab who is interested in the application of RNAi to another brain disorder … brain cancer.

How involved in the road to therapeutics would you like to get? A lot of times stuff that happens at a research lab gets passed off to companies.

I’d like to stick with it, mostly because I think it’s a learning experience: We go from the bench hopefully to some sort of phase I trial, and we learn from that trial. I don’t know that we can hit a home run — I’m sure there’s going to be things that we need to tweak, and [then] you go back to the bench. I think it’s the back and forth process that really excites me. We have to learn from experiments that don’t quite hit a home run the first time — we’ve got to work our way around the bases.

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