Professor Yanick Crow: Testing a new treatment for Aicardi–Goutières syndrome
Image Courtesy of Yanick Crow & The University of Edinburgh
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Professor Yanick Crow and his team at the MRC Human Genetics Unit in the Institute of Genetics and Cancer at the University of Edinburgh are working on understanding rare diseases to better diagnose and treat them, with a particular focus on a rare genetic disorder called Aicardi–Goutières syndrome, or AGS.
Yanick: So this is a disease of children. It affects their brain function. The children can present variably, but the classical presentation is that after a few months of life where the child is apparently well or not doing very badly, the child becomes very unwell and cries inconsolably for several months, stops feeding and loses skills, all of the skills essentially that have been acquired up until that time in the first few months of life.
Yanick: So it's a devastating illness and very difficult for the families. And not infrequently, these children will go to the doctor. The parents will be told, oh, it's colic or teething, or this kind of thing.
Yanick: And it takes a while before people realise that there's something very significant going on as the skills are lost. Then usually there's a set of investigations that are done, imaging of the brain, some blood tests, maybe what's called a lumbar puncture, where we examine the fluid that sort of surrounds the brain, and usually the diagnosis is clinched genetically.
Yanick: Unfortunately at this time it's a disease where there are no -well, treatments are sort of starting to come online - but where there's no accepted therapy and no easy therapy and where, in fact, this is a situation where early diagnosis is very important because, if you make the diagnosis, some period of time after the disease presents already, the children have accrued a significant amount of neurological damage. And of course, it's very difficult to go backwards, so to speak.
Kat: So what's actually going on in this disease when we look under the hood in molecular and biological and genetic terms.
Yanick: So the disease is very interesting from a scientific point of view. And I'll sort of step backwards just for a second and think about Covid.
Yanick: So Covid is just one example of a virus where we have to recognise the virus to mount an immune response against the virus. And we recognise viruses by recognising their genetic material, and that allows us to then trigger an antiviral response through a molecule called interferon. So interferon is a kind of antiviral disinfectant, and it kills viruses.
Yanick: And evolutionarily speaking, that's not a bad way of trying to fight virus, but it does beg a conundrum, which is that if you're going to sense viral DNA as the trigger for an immune response, how do you differentiate your own nucleic acid from that of a virus? And because nature is clever, we've developed ways of trying to make sure that you don't misrepresent your own DNA as that of a incoming pathogen. And essentially in Aicardi-Goutières Syndrome of which there are at least nine genetic forms, what happens is there are mutations or changes in a piece of DNA, a gene that codes for a protein, which is a chemical which do stuff, and all of these chemicals that are associated with Aicardi-Goutières Syndrome are involved in making sure you don't misrepresent yourself as non-self.
Yanick: And so essentially in this disease you've got these genetic changes, which mean that the protein doesn't function properly. And then these children produce lots and lots of interferon all of the time. So that much interferon signalling over a long period of time is noxious and damages the cells and the tissues.
Kat: So tell me about the approaches that you and your colleagues are taking to try and find and test treatments for these patients.
Yanick: So at the moment, in particular in Edinburgh, we have got a funding from the Medical Research Council, the MRC, to run a clinical trial in Aicardi-Goutières syndrome, which involves children across the UK in four centres: Edinburgh, Manchester, Great Ormond Street and Birmingham.
Yanick: And in that trial, we're doing something that sounds slightly like science fiction, where we're using drugs that are have been used for 30 years or so in millions of people to treat HIV. So we're using drugs that are called RTIs or reverse transcriptase inhibitors. And the reason for using those drugs is those drugs are normally used to inhibit the lifecycle of the HIV, human immunodeficiency virus, and they actually work very well.
Yanick: So that's a virus that's coming from the outside. But it's very interesting if you look at the human genome, about 40% of the human genome is said to be composed of ancient virus, which has integrated itself within the human genetic material, and they still want to do their thing, which is basically reproduce themselves.
Yanick: And instead of using the RTIs to affect a virus that's coming from the outside, we're using the RTIs on the basis that can affect the lifecycle of viruses that are on the inside, and the hypothesis is that those viruses on the inside are actually driving the interferon response.
Kat: That is so fascinating. I've long been aware of sort of our internal junk DNA and how much of it is made of these long dead viruses and that they're may be not as dead as we think they are.
Yanick: No, and there's an awful lot of them. There's an awful lot of them, I mean, it is a tremendous amount of genomic material and it's sort of not surprising perhaps.
Yanick: And in fact people are implicating these retroviruses in things like ageing and other autoimmune inflammatory disorders.
Kat: So where are you at with this trial so far?
Yanick: So the trial's launched and been recruiting patients since late summer last year, and so it'll be running into the summer of 2024.
Yanick: And currently we've recruited three patients in Edinburgh, one patient in Great Ormond Street, and the other centres are just about to open. So we hope to recruit up to 24 patients. And I think it's very important to recognise and thank and be grateful to the families that become involved because it's very hard to have a child with problems that, you know, not just from an emotional point of view, but from a very practical point of view: getting to places, getting in and getting out of the house, difficulties with staying over, these kinds of things. So it's an enormous undertaking and it's always remarkable and humbling how the families do want to get involved. So, in fact, in terms of numbers, there aren't that many patients in the UK, but there's more than 24 and I think that we'll have no problems recruiting as long as we have enough time for the trial to run.
Kat: That’s Professor Yanick Crow. And thanks to my other guests, Natalie Frankish, Professor Zosia Miedzybrodzka and Dr Joe Marsh, and also to Dee Davison and the team at the MRC Human Genetics Unit for supporting this episode.
