Institute of Genetics and Cancer

Reverse transcriptase inhibitors in Aicardi-Goutières syndrome

A study into the use of reverse transcriptase inhibitors for the treatment of Aicardi-Goutières syndrome. December 2018.

Brain images
The New England Journal of Medicine ©2018.

Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with increased levels of a chemical called type I interferon. Normally, we only produce interferon when infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code in these individuals, the cells in the body are fooled into thinking that the person’s own DNA and RNA is viral – that is to say, there is a confusion in telling ‘self’ from ‘non-self’.

A large portion of our own DNA is made up of ancient virus (‘endogenous retrovirus’), that has been incorporated into our genetic material over millions of years – sometimes referred to as junk DNA. Some of these endogenous retroviruses still have the potential to act like a virus coming from outside of the body, so that they need to be controlled. Researchers in the Centre for Genomic and Experimental Medicine wondered if the mutations causing AGS mean that these normal control mechanisms don’t work. If 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 body. 

Reverse Transcriptase inhibition model

Since repair of the genetic code in every cell would be impossible, the group decided to treat AGS patients with reverse transcriptase inhibitors (RTIs). RTIs are used to combat the HIV-1 virus that causes AIDS. In the case of AGS it was hypothesised that the same drugs might be able to control endogenous retroviruses driving interferon production. Published in the New England Journal of Medicine, the team of Professor Yanick Crow observed a reduction in interferon levels in affected patients treated over 12 months, with levels of interferon increasing again when treatment was stopped. They also recorded a change in cerebral blood flow during the period of therapy, suggesting that the drugs might be having a functional impact at the level of the brain.


Although preliminary, these results are consistent with the idea that ‘junk’ DNA can sometimes be associated with human disease. RTIs are very safe drugs, that have been used in millions of people around the world, and so we are keen to extend our exploration of their therapeutic possibility in AGS. More broadly, our results indicate that it might also be worth thinking about treating other diseases associated with increased levels of type I interferon in this way, such as the immune condition systemic lupus erythematosus.

Professor Yanick CrowCentre for Genomic and Experimental Medicine, University of Edinburgh

Publication in New England Journal of Medicine DOI: 10.1056/NEJMc1810983

Professor Yanick Crow's Research Group