Abandoned cholesterol drug fights nasty gut parasite

Cryptosporidium is a common intestinal parasite. Usually picked up from drinking water, it infects the cells lining the gut, causing pain and diarrhoea symptoms which can go on for weeks. In some groups though, it’s particularly risky - very young children and people with weakened immune systems can develop severe and sometimes life-threatening infections. And the problem is made worse by the fact that we have no proven remedies to date. But now, scientists at the Francis Crick Institute have taken an extraordinary step: by using CRISPR gene-editing to switch off one by one almost every gene in cultured human intestinal cells, they’ve been able to find out genes need to be operating in a cell either to boost or limit the growth of Cryptosporidium. This has enabled them to comb through our existing repertoire of drugs for agents that target the same genetic pathways in our cells, and they’ve found one: an old, since abandoned, cholesterol-lowering drug that can significantly impede the growth of the parasite, both in culture and in animal tests. Here’s Bishara Marzook…

Bishara - So we are looking for a cure or a treatment for cryptosporidiosis, which is an intestinal parasite that infects children under five and immunocompromised people around the world.

Chris - There was a problem with that in the southwest in the last year or so, wasn't there?

Bishara - Yes, definitely. So people in Devon, sort of May last year, were all told to boil their water supply because it was believed to have been contaminated with cryptosporidium.

Chris - Where does it come from then? If it was getting into drinking water, what's the natural source of cryptosporidium?

Bishara - So there are different species that infect different organisms, but the outbreak that happened in Devon, we believe would have been Cryptosporidium parvum, which is a species that infects ruminants, so cows, lambs, sheep. So we get a lot of outbreaks as a zoonotic transmission. So that's going from animals to humans.

Chris - So what, it spills over from the animal if you get contamination of the water supply with, say, faecal material, that's how it would get in?

Bishara - Exactly, yes.

Chris - And when a person has it, what sorts of symptoms does it cause? If you are a healthy adult, you would probably have stomach cramps and diarrhoea?

Bishara - So yeah, for about maybe two or three weeks. But if you are a young child, say under two years old, or if you have problems with your immune systems, this can be sort of uncontrolled diarrhea for prolonged times.

Chris - And do we have any treatments at the moment for it?

Bishara - At the moment, there is only one drug that's approved for treatment. It's called nitazoxanide. But unfortunately, it actually doesn't work as well in the people that need it most: in young children or in immune suppressed people as well.

Chris - And hence, you were going looking for something that might work better.

Bishara - Exactly, yes.

Chris - And how have you approached it?

Bishara - So the problem with cryptosporidium is there's very little known about it already. Research on this parasite is lagging behind other more well-known parasites like malaria or toxoplasma. So we actually just set out to understand what about ourselves the parasite really needs. So cryptosporidium is a parasite that lives in the cells of our gut. So we just asked, what do our cells provide that the parasite needs? So we disabled almost every gene that our cells express one by one and then asked the question, how does this affect the parasite?

Chris - And your rationale is, I suppose, if you disable the genes one by one and you find out whatever it is that the parasite's relying on in our cells, you can then say, well, are there any drugs that will do that for us that would therefore probably work against the parasite?

Bishara - Exactly. So what we really wanted to find would be something that our cells make that there's already a drug designed to target for maybe a different reason.

Chris - And did you find some genes that you could disable that would disable the parasite?

Bishara - Interestingly, we found some genes when we knock them out, the parasite didn't grow as well. But some other genes, when we knock them out, the parasite actually grew better. So we actually then honed in on one particular gene that made one metabolite that growth of the parasite seemed to hinge on. And luckily, because this gene is in the cholesterol biosynthesis pathway, a drug company had already been interested in it maybe kind of 20 years ago as probably an alternative to the statins that everyone uses. And so a drug had already been developed to target this gene.

Chris - And does it work if you give that drug? Does that drug then mimic this effect of knocking out the gene? And does that disable cryptosporidium?

Bishara - It does. So in a dish, we tried this drug and it seemed to work and then we moved it to mice. So we infected mice with Cryptosporidium and then treated them with this drug and it reduced parasite growth in the mice as well.

Chris - How good is it? Does it reduce the parasite growth by a meaningful amount? As in, were you a person struggling with this because you're HIV positive and immunosuppressed or you are a very young child, would it be the difference between chronic diarrhoea and being better?

Bishara - It's hard to translate mouse studies to human studies. So we are hoping to take this to human studies next. But in the mice, in our particular immunocompromised mouse model, it was able to reduce the parasite by more than half. And it also reduced the intestinal damage that we see that is a hallmark of this parasite infection as well.

Chris - And is the next step now to do a human clinical trial to see if you can break the back of a person who's got chronic Cryptosporidium infection with this?

Bishara - Yes, exactly. So we're working with some collaborators right now who are used to running clinical trials in endemic regions. So yes, we're very much looking forward to trying this out. And the nice thing about this drug is it already has gone all the way up to phase three clinical trials. So there's already a lot of safety data as well behind it. So we're hoping to fast track the tests in humans and in children.