New Hepatitis C treatment, maybe!

I was having a virus discussion with a surgeon recently:

Me-- People think to do HIV-1 research you have to gown up in those crazy suits and do all this insane safety stuff, really, the only thing I do 'really' different is I wear *two* pairs of gloves, lol!

Her-- I always double glove too, but its not the HIV-1 Im most worried about. Its Hepatitis C.

HIV-1 researchers, surgeons, people at high risk of accidental exposure to HIV-1-- we always have antiretrovirals within 5 feet of us, just in case. Get stuck with a needle, take the pills NOW, and you can stop the infection from getting a foothold. Worst comes to worst, there are lots of antiretrovial options available in the US now.

Hepatitis C is a different story. Theres not a whole hell of a lot physicians can do for you. *Maybe* you will get better. Or maybe you will be one of the millions of people who get liver cancer/cirrhosis and get put on the liver transplant list... which still wont 'cure' you. 10-20K people die from HCV complications in the US every year.

Now, we do have drugs to treat HCV. By 'drugs', I mean, 'two drugs'. Interferon and ribavirin, and they do help... some people (its complicated). Some people cant finish the treatment cycle because it makes them go crazy.


So any potential new therapy is really good news. This particular new treatment also has some pretty sweet side-effects:

Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus

Hepatitis C, like all viruses, has to hijack your cells to produce baby viruses. This makes them hard to treat-- you cant mess up a viruses life cycle without messing up a normal cellular process.

Scientists noticed a host cell microRNA, miR-122, was super up-regulated in HCV infected cells. Apparently, HCV needs miR-122 in order to reproduce. So, if we could 'mess up' miR-122, we could mess up HCV infection.

Scientists worked out this neat trick to get a strand of DNA complementary to miR-122 into cells (they call it SPC3649, doesnt matter). This strand smushes itself up to the miR-122, and the whole thing gets degraded, thus lowers cellular levels of miR-122. They put this mix on cells in tissue culture, and YAY! They knocked down production of hepatitis C viruses!

Of course, 'curing' HCV in tissue culture doesnt mean much, so these scientists then tested their treatment in mice. It worked!

Of course, 'curing' HCV in mice doesnt mean much, so these scientists then tested their treatment in a non-human primate, African Green Monkeys. It worked!

Of course, 'curing' HCV in AGM doent mean much, as the only other primate that gets the same hepatitis C pathology as humans is chimpanzees. So in this paper, these scientists tested their treatment in chimpanzees.

It worked!... at the highest doses. Aaaand it doesnt look like HCV was evolving resistance to the treatment (its an RNA virus guys, QUASISPECIES!)!


And the chimps appeared to be pretty much fine. No obvious, crazy, SPC3649 abnormalities... except for one thing.

I mean, miR-122 isnt hanging out in liver cells just for the hell of it. It has a function, and this treatment interferes with miR-122s normal function. Know what the side-effect of SPC3649 is? 25-54% lowered cholesterol levels. BAD cholesterol levels.


Considering the shit we have to deal with with antiretrovirals, this is a pretty damn convenient side-effect!


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You know, I had no idea that Hepatitis C was that nasty.

I didn't assume you spend all day in the big hazmat suit, but srsly? Two pairs of gloves? That's it?!

I mean, stop and about it for a second and it makes total sense. But it kinda blows the intuitive mind.

Well, the whole Hep-C thing is interesting, but what is surprising to me is their ability to get oligonucleotides into cells at therapeutic levels. How'd they do that?

I thought *that* technical hurdle was a huge barrier to possible treatments of an enormous number of diseases/conditions with cDNA drugs. Was there some breakthrough recently that I missed?

Simon-- Yeah, youre pretty much screwed once you get older, or have already gotten a transplant...

OP-- HIV-1 is only BSL-2 :) But I work with it in a BSL-3 lab, so I have to do a few extra things that arent technically necessary. Lab coat (just for the BSL-3, it never leaves that lab), goggles, mask (not necessary for HIV, but for the lab), and two pairs of gloves!

Divalent-- Its some magic voodoo. 'Locked nucleic acid (LNA)-modified oligonucleotide'. And they just administered it IV. I mean, no direct injection into the liver or anything! I dunno!

I thought double gloves were like double condoms - MOAR likely to break than singles.

But that is just a vague Cosmopolitan Magazine recollection, nothing scientific.

ERV, you make some great points in this piece - the best of which are that the findings in mice and monkeys didn't mean much, begging the question why these experiments were done in the first place. However, crucially, the findings don't mean much in chimps either...
Chimps DON'T get the same pathology when infected with HCV as humans: there are different rates of chronicity & viral clearance, different immune responses, different progression to fibrosis and cirrhosis, etc...meaning that something very different is going on. Chimps don't serve as good models for human diseases: take HIV - all the 90 or so vaccines tested to date have been tested in chimps, yet none works in humans. Again, different pathology is at the root of this.
The fact is that the tissue culture experiments were undoubtedly more relevant to human response that any of the animal work. Further, this drug is already well into clinical trials - so why do the chimp experiments?

We need to learn that science could, and should, progress in a human context without recourse to poorly relevant and inhumane experiments on chimps. Don't forget that nobody outside of the U.S. uses chimps - so they can't be that useful, right?!

JB-- If it doesnt work in tissue culture, you dont bother trying it in mice. If it doesnt work in mice, you dont bother trying it in monkeys. If it doesnt work in monkeys, you wouldnt bother trying it in chimps. If it doesnt work in chimps, you dont bother trying it in humans.

Do you understand that?

Do you understand that we dont waste lives unnecessarily?

Do you understand that we dont take things straight from 'Hey, I got an idea!' to 'LETS KILL SOME FUCKING CHIMPS!'?

Notice how many chimps they used in this study?

Four. Because we dont want to waste lives unnecessarily.

And Im not even going to bother addressing your comments about virology/non-human primates. Normally I would correct reader errors/questions, but apparently youre trying to 'lecture' me, a fucking virologist, on this topic. Please, dipshit, please tell me about HIV-1 and vaccine design, especially in chimps. If youve read ERV for more than a week you would know why thats stupid and you dont know what the fuck youre talking about.

Youre an idiot. A self-righteous idiot that lives off the hard work and sacrifices of others, including animals that have been sacrificed to make your life better.

"all the 90 or so vaccines tested to date have been tested in chimps, yet none works in humans. "

Nonsense, only a few of the early vaccines were tested in chimpanzees, and chimpanzees were largely abandoned in AIDS vaccine research in the 1990's due the the differences in pathogenicity you refer to. Even where SIV and SHIV in macaques (the favoured models in AIDS vaccine research) are concerned the results of vaccine tests in monkeys have often been very mixed, with none of the vaccines which failed in Large scale human trials vaccines provided any useful protection against the more virulent R5 tropic strains of SIV that are considered the best macaque model or HIV infection by most researchers these days.

Chimps don't get exactly the same hepatitis C pathology as humans but they get one that is very similar, certainly good enough to be very valuable for evaluating candidate vaccines and medicines.

Erv's point in discussing the various steps inn the evaluation of SPC3649 is to show how the study progressed as the evidence for the usefulness of SPC3649 got better and it faced tougher tests. I think Erv may have made a mistake though, while SPC3649 was assessed against Hep C in vitro the evaluation in mice and african green monkeys only looked at its ability to safely and effectively antagonize miR-122, and not at its ability to suppress viremia. That test had to wait until the chimp studies that were announced this week. Neither mice nor African green monkeys develop disease when infected with Hep C.*

SPC3649 has so far only completed early safety tests in human volunteers, not any kind clinical trial to assess its efficacy against Hep C. The results of this chimp study provide strong evidence to support taking SPC3649 into larger efficacy trials in human Hep C patients.

* Though transgenic mice that can be infected with Hep C have been developed and are likely to become more important in future.

I'll answer truthfully for JB:

Do you understand that?

Nope. Not a single bit.

Do you understand that we dont waste lives unnecessarily?

Nope. I thought that scientists just loved to torture animals.

Do you understand that we dont take things straight from 'Hey, I got an idea!' to 'LETS KILL SOME FUCKING CHIMPS!'?

Nope. I know nothing of science or it's procedures, I just think its wrong because.... because.... because I think it's wrong!

Joshua beat me to my question, whether this would be a viable treatment for people with high Ldl levels.

By BeamStalk (not verified) on 08 Dec 2009 #permalink

Joshua, BeamStalk-- Its in Phase I of testing right now, and I believe that these healthy folks are seeing drops in LDL.

But this kind of treatment would be transient (you wouldnt go on SPC3649 forever for HCV, like you have to with anti-HIV drugs). Not sure how it would work for LDL levels-- Maybe a shot of SPC3649 once a year or something? I dunno, but Im sure they will figure something out if the rest of SPC3649 side-effect profile is good!

WMDKitty-- Its only at Phase I. Its gonna be a while. :(

Statins, so I understand, are fairly safe so SPC3649 would have to be a bit special to replace them. Maybe as a quick-fix for people with high cholesterol levels, whilst they get dieting?

we dont want to waste lives unnecessarily.

Hence our objection to JB.

Oh yeah. Oh HELL YEAH! I was wondering if anyone had come up with a way to block miRNA in a whole animal and now I see someone's way ahead of me. And as simple as locked nucleic acids to boot. Hell, I was going to use the damn things as PCR primers and you can just inject them as treatment straight up? No wonder they got into Science.

This kind of thing opens up a dementedly huge array of treatment possibilities from viruses right on to cancer. Might be some targetting issues for some miRNAs, but it's a great start. I wouldn't be surprised if there's a Nobel prize for this somewhere....

As for the HDL levels, it may be a good replacement for statins in people who don't tolerate them well, though a regular injection over a pill might be a bit of an issue, and there may be some very long term side effects, I guess we'll have to see.

LNA?! The hell?!

The guy who invented those is my uni. (Well, technically not my uni anymore.)

The cholestorol is interesting, too. That's usually one to make 'Big Pharma' sit up and take notice. I'd ask Derek Lowe, but I still need to read through the 100+ replies to his Climategate(gategate) post and come up with a coherent reply.