Reverse Transcriptase Inhibitors (RTIs) in
Aicardi–Goutières Syndrome (AGS)

Overview

Reverse Transcriptase Inhibitors (RTIs) are part of the cocktail of medicines used to treat HIV. So what do they have to do with AGS and why are we starting clinical trials? As strange as it seems, the answer is straightforward and has to do with how our immune system senses and responds to viral infection.

Viruses

Many AGS families know that viruses can be troublesome, but why? The pathways and signals of the immune system that become overexcited in AGS belong to our early warning system, our 'innate immunity.' Our cells are always on the lookout for signs that they are infected by viruses by monitoring for a buildup of genetic material (or "nucleic acids"). When viruses take advantage of our genetic machinery, they don't play nice or clean up after themselves and cause a lot of problems.

Innate Immunity

Our cells sense the buildup of nucleic acids from viral infection and sound the alarms using molecular signals. There are many different cells involved in responding to these signals (and perhaps even more signal types), but this cascade leads to the inflammation that damages the brain and other organs. To a significant degree, AGS involves a malfunction in this system we use to properly identify and respond to viral infection.

DNA Parasites

You may have heard of the term 'Junk DNA' or that only 2% of our DNA codes for proteins that manage the processes of life. The truth is more complex, but almost half of the human genome appears to be the useless remnants of ancient viruses. Our cellular ancestors struck a bargain with or were parasitized by genetic material that does not spread externally like infectious viruses do. Rather, this parasitic DNA uses our machinery to continually amplify itself by incorporating more and more copies back into our DNA. We don't exactly need it but we can't get rid of it.

AGS and Junk DNA

Our cells would respond to this 'junk' genetic material as a viral infection if we did not evolve methods to deal with it. Disruptive mutations in AGS genes throw this system out of balance. SAMHD1 actually inhibits reverse transcriptase, while some AGS genes actively cleanup genetic material. ADAR1 tags this material so the viral sensor IFIH1 doesn't react to it. And, the more recently identified AGS genes are involved in DNA packaging, a sort of housekeeping process that keeps unwanted DNA from being read by packing it up in storage. If these genes fail to do their jobs, AGS cells react.

Retroelements and Reverse Transcriptase

"Retroelements" make up most of this parasitic DNA, and there are a few different kinds. One type of retroelement (LINE1) uses a "reverse transcriptase" enzyme to insert more copies of itself back into our DNA. This effectively allows the retroelements to clone themselves, so that more and more copies will get made. Reverse transcriptase is the same process and enzyme that HIV uses, and drugs were developed that interrupt it ("reverse transcriptor inhibitors" or RTIs).

AGS and RTIs

With RTIs in AGS we hope to reduce the proliferation of retroelements and the accumulation of genetic "junk," ultimately turning the volume down on the AGS alarm signals. Some early studies demonstrate that RTIs do reduce interferon stimulation in AGS, and clinical trials are just starting to ramp up. We don't know yet whether the effect will be enough to have a clinical impact on individuals with AGS, but it's possible this could become part of a combination of medicines. Because RTIs don't directly suppress the immune system, they could be safely combined with drugs that do, like JAK inhibitors.

RTIs and Clinical Trials

As of February 2023, there are 3 AGS clinical trials with reverse transcriptase inhibitors either active or about to begin in Europe and the United States. They may not be open to every AGS genotype due to some of finer details of AGS genes and retroelement types, but the Children's Hospital of Philadelphia is doing lab extra experiments to verify which types of AGS are likely to benefit.

 
 

Clinical Trials

Clinical trials for Aicardi-Goutieres Syndrome can be found on our Clinical-Trials list and at https://clinicaltrials.gov/. Continued use of JAK inhibitors like baricitinib and ruxolitinib should be allowed in all three of these trials.