AGS is a Mendelian disorder of aberrant immune activation. Growing evidence

suggests that an accumulation of endogenous nucleic acid species, perhaps derived from retro-elements, provokes a type I interferon response with subsequent recruitment of the adaptive immune system. The disease is associated with significant morbidity and a high rate of mortality. Designing effective therapeutic approaches will be enhanced by an improved understanding of disease pathophysiology. Following proof-of-principle studies in the Trex1-null mouse, treatment strategies of immediate interest include type I interferon blockade, interruption of the generation of the products of reverse transcription and a depletion of B and T cells. Therapies already exist relating to each of these strategies. In the future, inhibition of Sorafenib molecular weight components of the relevant cytosolic signalling pathways (for example, in the case of TREX1 – cGAS, TBK1, STING and IRF3) might also represent

attractive targets. The difficulties of randomization and controlled studies in rare disorders with small populations are relevant to AGS. It may be useful to consider using an historical cohort as a control population in a treatment trial; to that end, careful attention to natural history is crucial at this time. Additionally, outcome measures to Selleck ITF2357 determine the effectiveness of treatments need to be established, and their best use carefully considered. Disease manifestations, e.g. radiological findings and clinical outcomes, are frequently difficult to measure objectively. Thus, the relevance and specificity of biomarkers needs to be established in anticipation of clinical trials. Combinations of

outcomes may prove to be the most useful. Therapy is most likely to be beneficial in the early stages of the disease, making rapid diagnosis of the utmost importance. However, ongoing disease and later-onset phenotypes mean that treatment will also probably have a role in at least some older patients. Unanswered questions as to whether one therapy will be appropriate for disease due to any genotype will become clearer as our understanding Cyclic nucleotide phosphodiesterase of AGS-related protein function improves and other animal models are developed. For example, the possibilities of using treatment with hydroxyurea to deplete the pool of deoxyribonucleotide triphosphates (dNTPs) might be relevant in the context of SAMHD1-related disease, but not other subtypes of AGS. Finally, it will be interesting to determine if treatments developed in the context of AGS are germane to other phenotypes including familial chilblain lupus, retinal vasculopathy with cerebral leucodystrophy and some cases of systemic lupus erythematosus. We thank sincerely the families and clinicians who have contributed to our collective work. Y.J.C. would like to thank Diana Chase for her expert proof-reading. Y.J.C.