Old drug boosts Covid resistance
We kick off this week with a topic that, thankfully, we've not had to talk about for a while, and that's Covid-19; and there's some good news, because researchers from Cambridge University have discovered that a very cheap, very safe drug, called ursodeoxycholic acid, that's already in routine use in the clinic for treating some forms of liver disease, temporarily turns off the gene for the chemical called ACE2 that the Covid-19 virus uses as a "doorway" to infect us. Taking the drug reduces the levels of this protein, which appears to make a person much harder to infect, and potentially retards the ability of the virus to cause disease. Fotios Sampaziotis is one of the team that spotted this could happen…
Fotios - It was a serendipitous finding. We were working on a mechanism to make the liver repair itself following damage. We were looking at a couple of drugs and we're trying to find what the effect of certain drugs was on liver cells: which genes get turned on and which genes get turned off. What we found every time was that ACE2, which is the formal name for the doorway that allows SARS CoV 2 (the Covid virus) to get into the cells, was turned off with these drugs each time. But we didn't quite know what to make of it and we kept ignoring it and moving onto the next one and the next one, which made more sense.
Chris - And you ignored it just because this is before the pandemic happened and it wasn't relevant to your research. So you just thought, "oh, I'll put that to one side. Not relevant."
Fotios - Absolutely. I'm not sure what this protein does, but I'm sure the time will come when we will find out, but we won't focus on that for now. And, true to that, the time did come. As soon as the pandemic hit, everybody started talking about this protein, which is the doorway to the virus and so important for the virus to get into the cell. And we thought, "hang on, we can modify this protein, switch it on or switch it off, and take it away. And if we take away the door, the virus will never be able to get into the cells."
Chris - It did emerge pretty quickly during the pandemic that ACE2 was this marker on the cells in the nose, in the throat, in the lungs, that the virus grabs hold of to get into cells and infect in the first place. So I suppose the light bulb must have gone off in your head. "We've got some drugs that we already know turn this thing off and just make it go away."
Fotios - Exactly. That's exactly what happened. And we thought "let's test it and see if it works on liver cells." It worked brilliantly. We put the virus on the cells and saw that we could absolutely block viral entry.
Chris - In the liver?
Fotios - We started in the liver. But then the next natural question is: it's not a liver disease, is it? It's a lung disease. So, let's go and test it on mini lungs, which we call organoids, in a dish. We produced some lungs in a dish, we infected them with the virus, we gave the drug, and we saw that we could block them with a drug. So we're quite happy now in the lab that it seems to be working on all the relevant cell types. And the biggest question then is, can we move from cells to a whole organism? So that's when we decided to test it in animals, in hamsters.
Chris - Why hamsters? Are they a good model for what would happen in a person?
Fotios - Usually, most people who do research work with mice, but mice do not get Covid. So the hamster became the model to use and it worked brilliantly. But of course it wasn't human. So the next step was to move even further and go into humans and human organs.
Chris - As in give people the drug and see if it turns off their expression of this ACE2 doorway for Covid?
Fotios - We wanted to see if it turns off the expression of the doorway, and if shutting down the door blocks the virus from getting in. We gave the drug to people, eight doctors in Germany. We measured the levels of the doorway before they took the drug for five days. We measured what happened to the doorway and we saw a significant reduction, but we didn't know whether or not that translated to the virus not getting in. So we took human lungs which were offered for transplantation, but they could not be used. We put them on a machine that essentially keeps them alive for several hours outside the body. In one lung we gave the drug, the other lung didn't get the drug, but we gave Covid to both the lungs. And what we saw is that lung that was receiving the drug got infected far, far less. And that was the closest we could get to actually giving the infection to a human organ.
Chris - Is another way to probe this - because you use this drug in the clinic - to say, "well let me look at my patients that I've got on this, an equivalent or similar patients that I haven't got on this, and ask, 'is there an excess of Covid in the people who are not on this drug?'" Because that's another way of asking that question in real human beings.
Fotios - That's spot on. So this is the final step of what we did because we did it in the clinic all the time. We asked exactly this question and the answer was yes. But of course you have to be very careful with these results because the patients who are taking the tablet versus the patients who are not taking the tablet can differ in many, many parameters. And some of these factors could affect the virus. Most likely it was a tablet that blocked them from getting the virus, but we cannot fully exclude that they were shielding more or that disease somehow rendered them less susceptible to Covid. This is why we need a clinical trial, which I think is where we're going next.