Sunday, November 27, 2011

DRACO: Death to the Virus

DRACO: Death to the Virus:

In a paper published 27 July [1], researchers from MIT reported successful tests in mice with a new drug that holds the promise of being a cure to all viruses. The drug, DRACO (Double-stranded RNA Activated Caspase Oligomerizer), works as a “broad-spectrum” antiviral, killing virus-hijacked cells by targeting double-stranded RNA produced in the viral replication process. DRACO proved successful against all 15 viruses tested “including rhinoviruses that cause the common cold, H1N1 influenza, a stomach virus, a polio virus, dengue fever and several other types of hemorrhagic fever.” [2]

We may expect results from cell trials against AIDS within the next 12 months.

DRACO is but one broad-spectrum therapeutic being developed as part of a project called PANACEA (Pharmacological Augmentation of Nonspecific Anti-pathogen Cellular Enzymes and Activities) headed by Dr. Todd Rider, senior staff scientist in MIT Lincoln Laboratory’s Chemical, Biological, and Nanoscale Technologies Group.

I met with Dr. Rider in the food court of the MIT co-op bookstore early on a weekday. He had already finished tending to his mice and, after we chatted, he rose to declare that he off to do “real work”… writing grant proposals to keep his research alive.

Could you give us a broad overview of the Panacea project?

Sure. We’ve come up with a broad-spectrum antiviral that we call DRACO, Double-stranded RNA Activated Caspase Oligomerizer (I love acronyms), and it’s basically designed to detect any long double stranded RNA, so we’ve created chimeric proteins where one end will detect the chimeric RNA — the double-stranded RNA — and then the other end will trigger apoptosis, or cell suicide. So the net effect is that these DRACO molecules can go inside all the cells in your body, or at this moment, inside all the cells in a mouse, and if they don’t find anything, then they don’t do anything. But if they find a viral infection, if they find a viral double-stranded RNA, then that will activate the back ends to trigger cell suicide, and that will kill the infected cell. That terminates the infection.

So there wouldn’t be a difference between DNA Viruses and RNA Viruses?

It works with both. We’ve tested it on both. All known viruses make double-stranded RNA, and that’s true from the literature and also true from our experiments. So here (indicating illustration) the viruses we tested included a couple DNA viruses, and it worked quite nicely against those. Others in the literature are also known to make quite a bit of double-stranded RNA. Other DNA viruses, like pox viruses and herpes viruses, also make double-stranded RNA.

Has it been tested on each family of virus?

It’s been tested on these families of viruses so far (indicating paper). There are a gazillion viruses, so we’re working our way through them as quickly as we can. It’s been tested on several very different families so far.

My understanding is that viruses usually kill the cell anyway, but retroviruses usually do not. I don’t know how viruses cluster. Are there any odds at all that there would be a retrovirus that clusters too tightly in a certain organ where it [triggered cell death by DRACO] would cause a lesion?

Virtually all viruses will kill the host cell on the way out. Of the hand-full that don’t, your own immune system will try to kill those infected cells. So we’re really not killing any more cells with our appraoch than we already have been. It’s just that we’re killing them at an early enough stage before they infect and ultimately kill more cells. So if anything this limits the amount of cell death.

So that’s not really a legitimate fear.

It shouldn’t be.

How far along are you and how far away are you from human trials?

Unfortunately quite a long way. We’ve done a number of tests in mice. We need to do more testing in mice. Of course, MIT is not a pharmaceutical company. There’s only so far we can take it at MIT. We’re hoping to license it to some pharmaceutical company, and they would carry to larger-scale animal trials. Usually the FDA wants to see a lot of mouse trials, which we’ve done already; and then a lot of trials in, say, rabbits or guinea pigs, and then trials in monkeys before they approve human trials. So, if a licensee takes this, if we have funding for it, it still might take a decade or so before it really is available for humans.

So how’s the funding working now?

We have funding from NIH [National Institutes of Health].

And can you take it up to monkey here [at MIT]?

We may be able to take it into further animal models here, but mice are the easiest thing to use. We have a lot of mice. We’re also limited by funding. We only haved NIH funding at the moment, and we only have enough funding for about 1 person, and we have 4 people total, counting me, working at the moment, so we’ve split the funding four different ways…

Has anybody reached out to you?

Nope. Not so far.

When I first read about this I thought this was an amazing story, that this would be front-page news in a couple of hours. Weeks later, I was thinking this must not have been a true story. That’s when I looked it up again and saw that it was indeed on the MIT site. What’s the relative lack of interest. There haved been articles, but I feel this is definitely front-page material.

Well thank you. On the funding front, I think there’s a ton of funding for very basic research — not applied research, trying to cure something, but basic research — Let’s go study this virus, see how this virus works in a little more detail. There’s a ton of NIH funding for that. On the applied front, if you are ready for human trials — so you’re 10 years more advanced than we are now — then there are government agencies and companies that will take it and take it to that final step. But in that long gap in between there’s very very little funding out there. So we’ve been struggling for all of 11 years now just working to get funding, and at the moment we’re just barely limping along.

This is a subset of PANACEA, right? Can you describe PANACEA?

PANACEA is a family of broad-spectrum anti-pathogen treatments. We’ve tested some others, we’ve tried to get funding for others. This [DRACO] is the one that is furthest along.

What are some of the others that look promising?

We have a number of others. [DRACO] is a broad-spectrum antiviral. We have other broad-spectrum antivirals. We also have other PANACEA treatments that we’ve adapted to go after other things. Like for bacteria. And of course there are antibiotics, but for bacteria that are resistant to existing antibiotics, such as tuberculosis, malaria… so we can adapt this to pathogens other than viruses. We’ve done some initial experiments, we just can’t get funding for that so far.

Do you foresee any potential wild-cards in the human trials?

It’s always difficult to tell what will happen. I hope that there won’t be. We’re always concerned that there will be some toxicity or other unforeseen problems. We’ve been very pleased every step of the way in the cell testing. We’ve tested in a number of different human cell types representing many different organs; human lung cells, human liver cells, all kinds of different human cells, as well as a variety of animal cells. We haven’t seen any toxicity or any other strange effects in any of those cell types. In the mice we were again very concerned about toxicity, and we haven’t seen any toxicity in the mice. We inject the mice with very high doses of the stuff daily for a number of days, and they seem fine. We let them move for a while, eventually we dissected them, looked at the tissues. All the tissues were fine, there’s no organ damage or anything. It’s always possible something unexpected could come up further down the road in monkies or in humans. We certainly hope not. But I think there is enough flexibility in the concept that even if there were a problem, there are ways to redesign the constructs that we have to overcome any potential problems.

That might also speak to the production cost. Is it fairly low production cost if, say, it was to be mass-produced in the future?

These are produced in bacteria, and at the moment I really don’t know what the ultimate production cost would be. We produce on a very small scale, barely enough for our mice. Of course cells eat a lot less DRACO than mice do. So if we’re producing for cells, that’s a very small quantity, but just a few flasks of bacteria will produce enough to last us for a while. But once you scale this up to a large-scale production large-scale animal trials or human trials, hopefully the cost would go down. I don’t know exactly what the cost would be.

Do you envision the final end-plan to be people with DRACO in their medicine cabinet, or more like penicillin today?

If it’s safe I’d like to see it used as much as possible for as many different things as possible. I would guess that if it were approved for human use by the FDA, initially they would be conservative enough that they would only want to see it used in very dire cases, just in case there are interesting side-effects or something, and it’s only to people with ebola or HIV that’s become resistant to other drugs who would get this. If this proved to be safe in those cases, then I would hope that they’d approve it for wider use against more common pathogens, perhaps all the way down to the common cold. And if it really is safe, then maybe you’d just pop a DRACO pill any time you felt a cold coming on.

How long does it stay in the system? It’s obviously not a vaccine –

Right. In cells it lasts at least for a couple of weeks, possibly longer. In the mice it lasts for at least 2 days. We have a lot of data in the paper showing it will persist in mice for at least 48 hours at fairly high doses in the tissues. This is really about trying to optimize that. There are a lot of tricks we can use to try to make it last longer if necessary. And if this stuff is truly completely safe, then you can give it prophylactically. You could even concievably give someone the gene for the DRACO so that their cells would just permanently produce the DRACO, and they would naturally be resistant to almost everything.

Oh, wow. That’s an amazing idea.


I feel like this is something that should be fast-tracked. We have all this planning in regards to epidemics. There is all kinds of scare that we’re ripe for an epidemic.

Perhaps we will be [approached with funding offers] in the future, but so far we haven’t been. We’ve really struggled along for the past 11 years, barely getting enough funding to stay alive.

So this has been on the table, at least as an idea, for 11 years?

Right. We just got good data from the mouse trials and published that, but 11 years ago we started engineering the DRACOs. Genetic engineering was a bit more primative in those days, so it took us a while to actually produce these things. Then it took us a while to produce and test them in cells. We ultimately tested against 15 different viruses in cells. As I said, we were kind of limping along for funding for much of that time, so we could only work on it when we had funding to work on it. For some fraction of our time, we had funding to work on it. Eventually, we were able to test against the 15 different viruses in cells in 11 different cell types. And then we had funding to do some mouse trials, got data, and then we got published.

If you get a cold this winter… are you going to be tempted?

I’m not tempted by colds. I’ve had very bad stomach viruses and I’ve been tempted to give myself the stuff to see what would happen.

You don’t think you’ll do that, though?

It wouldn’t be enough anyway. We only produce enough for mice, and for a human you require a much larger dose than for a 20 gram mouse.




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