2015

Aicardi-Goutières syndrome is a genetic disorder associated with inappropriate activation of the immune system.

A growing body of evidence suggests that an accumulation of nucleic acid (RNA and DNA), possibly derived from ancient viruses included in our own cells, would elicit an immune response orchestrated by type I interferon. Aicardi-Goutières syndrome is a serious disease that requires the development of treatments. The development of effective therapeutic approaches will be promoted by a better knowledge of its mechanisms. Following proof of principle studies carried out in diseased Trex1-null mice and thanks to new knowledge concerning the proteins associated with Aicardi-Goutières  syndrome, strategies of immediate interest include blocking type I interferon and other components of the inflammatory pathways, disrupting the production of ’reverse transcription’ products and decreasing white blood cells.

There are already treatments related to each of these possibilities. In particular, we will talk about a clinical trial of reverse transcriptase inhibitors, which is starting in France. Aicardi-Goutières syndrome is no exception to the difficulties of recruiting for the performance of controlled studies of rare diseases affecting small populations. It might be useful to consider using a historical cohort as a control population in a therapeutic trial. This is why it is currently crucial to pay special attention to the natural course of this pathology.

In addition, criteria for evaluating the effectiveness of treatments must be established and consideration should be given to their best possible use. Manifestations of this syndrome – eg. imaging observations and clinical outcomes – are often difficult to measure objectively. Therefore, it is necessary to establish the relevance and specificity of the biomarkers for these future clinical trials. From this point of view, we are particularly interested in the detection of an “interferon signature” in almost all the cases of Aicardi-Goutières syndrome analyzed to date.

Treatment will most likely be of benefit in the early stages of the disease. Early diagnosis will therefore be of crucial importance. However, the characteristics of the later-onset disease (eg, frostbite in some patients) mean that treatment is also likely to have a role in some older patients. Uncertainties regarding the suitability of treatment for Aicardi-Goutières syndrome based on genetic type will begin to dissipate as our understanding of the protein function associated with this disease progresses.