Children with Aicardi-Goutières syndrome produce high levels of interferon—a chemical normally reserved for fighting viral infections—even when no virus is present. This happens because genetic mutations trick the body into treating its own DNA as foreign, triggering continuous immune attacks that damage the brain. The problem is that much of human DNA consists of ancient viral remnants called endogenous retroviruses, often dismissed as "junk" DNA. The researchers suspect that in AGS, these dormant viral elements start copying themselves, mimicking an outside infection and driving the harmful interferon production. If this is correct, it would reveal that junk DNA can directly cause human disease. The team is testing whether reverse transcriptase inhibitors (RTIs)—drugs already used safely in millions of HIV patients—can stop these endogenous retroviruses from replicating. Early results from a one-year study showed interferon levels dropped while patients took the drugs and rose again when treatment stopped. If confirmed, this approach could also be applied to other diseases linked to high interferon, such as systemic lupus erythematosus, a much more common autoimmune condition.
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Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Normally, we only produce interferon when we are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code (contained in our 'DNA') in these individuals, we believe that the cells in the body are fooled into thinking that the person's own DNA is viral - that is to say, there is a confusion in telling 'self' from 'non-self'. In fact, a large amount of our own DNA is made up of ancient virus ('endogenous retrovirus'), that we have taken into our genetic material over millions of years - sometimes referred to as 'junk' DNA. These endogenous retroviruses can still act like a virus coming from outside of the body, so that they need to be controlled. We have wondered if the genetic changes causing AGS mean that these normal control mechanisms don't work. If that was true, the endogenous retroviruses would start to make copies of themselves which could be recognised by our immune system as 'foreign', leading to the continuous production of interferon which then damages the cells in our body. Since we cannot repair the genetic code in every cell, we wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, we are not treating HIV-1, but we wonder if the same drugs might be able to control endogenous retroviruses that we think are driving interferon production. Indeed, using this treatment in a recently completed study we gathered early information to suggest that we did see a reduction in interferon levels in patients over a one year period, with levels of interferon increasing when we stopped the drugs. Additionally, from a scientific point of view, these studies are of great potential importance for patients with AGS and their families. Scientifically, our project will be of considerable interest if the results support the possibility that junk DNA can sometimes be associated with human disease. RTIs are very safe drugs, that have been used in millions of people with HIV-1 around the world. If our results turn out to be convincing, we believe that it might also be worth thinking about treating other diseases that have also been shown to be associated with increased levels of type I interferon, including the much more common immune condition called systemic lupus erythematosus.
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