Abstract
Aicardi-Goutiéres syndrome (AGS) is a severe, often lethal genetic autoinflammatory
encephalopathy. It typically has an infantile-onset and results in progressive and profound
cognitive and physical disability. There is an urgent need to find an effective therapy for AGS, but
currently, there is no FDA-approved therapeutic approach that effectively alters the pathological
course of this disease. Clinical trials with IFN pathway inhibitors, such as the Janus kinase (JAK)
inhibitors baricitinib and ruxolitinib, have been carried out in AGS; these JAK inhibitors reportedly
resulted in improved systemic manifestations. However, their efficacies in treating brain injury, the
most critical pathological change of AGS, are very limited or ineffective.
There is a gap in AGS therapy development due to the relative rarity of this disease and not
available of an animal model that recapitulates the pathologic features of AGS, especially the
innate immune activation in the brain. We recently created a series of mouse models that
reproduced AGS's genetic, clinical, and pathological features of the brain, including innate
immune activation in the brain. With these AGS mouse models, we have found that the FDA very
recently (2022) approved JAK inhibitor, the tyrosine kinase 2 (TYK2) inhibitor Deucravacitinib,
and the TANK Binding Kinase 1 (TBK1) inhibitors sufficiently block innate immune activation in
the brain cells of AGS mice. Based on our preliminary data and findings from recent publications,
we hypothesize that selective inhibition of the type I IFN signaling pathway and TBK1 will more
effectively diminish the innate immune activation in AGS brains and improve the outcomes of
AGS treatment. In this study, we will address two Specific Aims. Specific Aim 1 is to test the
efficacy of deucravacitinib and compare it with baricitinib and ruxolitinib to find which drug is the
best medicine for AGS. Specific Aim two is to determine the significance of the JAK-STAT
pathway in AGS development via analysis of Adar1mut and STAT1/2-/- double mutant mice and
evaluate the effect of TBK1 inhibitor in mitigating neuroinflammatory phenotypes in AGS mouse
models.
In summary, this study will establish a preclinical approach in animal models to assess AGS
therapy. It will provide in vivo evidence to support the repurposed use of JAK inhibitors for AGS
treatment. It will also explore new drug-targeting sites for AGS and other interferonopathies.