Aicardi Goutières Syndrome (AGS) is a leukodystrophy characterized by early neurologic disability. While genetically heterogeneous, all genotypes activate a common pathway: interferon (IFN) production leading to Janus kinase (JAK) activation and transcription of IFN-stimulated genes (ISG). My preliminary work supports that there are two distinct phenotypes of AGS: a severe form characterized by global impairment and a milder form characterized by spastic paraparesis with preserved cognition. In our leukodystrophy center, we follow more than 100 children with AGS, two-thirds of whom are affected by the severe form. Despite a general understanding of AGS and growing interest in therapy development, progress has been limited by the lack of appropriate assessment tools. Because of sustained IFN expression, we hypothesized that children with AGS may respond to anti- inflammatory medications. In 2016, we launched a therapeutic program using baricitinib, a JAK inhibitor. Our preliminary results suggest that baricitinib decreases IFN-stimulated gene expression (ISG score by standard mRNA assay) and improves symptoms such as irritability and skin inflammation as reported by a symptom diary. While most families report neurologic improvement, preliminary results from traditional outcome measures are inconclusive. As supported by our equivocal findings, there is a critical, unmet need for (1) the ability to predict neurologic trajectory and therapeutic responsiveness at disease onset, (2) a novel, disease- specific outcome measure that is sensitive to neurologic change and clinically relevant to this unique population, and (3) the characterization ISG scores as an AGS biomarker. Our parallel treated and untreated cohorts will allow me to establish the value of these novel measures in defining both the neurologic trajectory and potential therapeutic response to baricitinib. The anticipated outcome of this proposal will be (1) a panel of features capable of predicting neurologic trajectory prior to therapeutic intervention, (2) a novel disease-specific assessment measure, and (3) a defined role of ISGs as a biomarker in AGS. These advances will be invaluable for future cohort selection and the evaluation of efficacy in future clinical trials benefitting AGS. With this final phase of intensive mentored training, I will be poised for success with future R01 applications related to the design of rare-disease outcome measures for children affected by leukodystrophies.!