Effects of Janus Kinase Inhibition in Two Children with Aicardi-Goutières Syndrome

Background/Purpose: Aicardi-Goutières syndrome (AGS) is a rare monogenic early-onset inflammatory encephalopathy that clinically resembles in-utero–acquired viral infection. Mutations in at least seven distinct genes have been identified in AGS patients. Analysis of the underlying molecular pathology has revealed defects in the metabolism and sensing of nucleic acids that lead to the inappropriate release of type I interferons (IFN). Type I IFN act on the IFNAR receptor and induce via the JAK-STAT signaling pathway the transcription of hundreds of IFN-stimulated genes (ISGs) that govern numerous inflammatory pathways. Since chronic type I IFN activation is a central contributor to the disease process, blockade of Type I IFN signaling through JAK inhibition may provide a potential therapeutic approach.