: Clinical Outcomes in Aicardi Goutières Syndrome

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Aicardi Goutières Syndrome (AGS) is a heritable disorder of excessive interferon (INF) production. AGS is a devastating rare disease occurring in fewer than 1/7000 live births that affects brain, skin, bone marrow and visceral organs. New data suggest that treatment with IFN blockade using Janus Kinase (JAK) inhibitors may be beneficial and further therapies inhibiting interferons are likely in the near future. Since opening our expanded access use program for baricitinib, a JAK inhibitor (NCT01724580), in February 2017, we have enrolled more than eighteen individuals, but lack appropriate qualified clinical outcome assessments (COA) or biomarkers to assess effect. We propose to use our participation in the multicenter consortium the Global Leukodystrophy Initiative Clinical Trial Network –GLIA CTN- to validate appropriate outcome measures and biomarkers in AGS. In this proposal, we will leverage the first approach to show therapeutic promise in AGS to concomitantly develop responsive outcome measures and biomarkers for future clinical trials. We will validate clinical outcomes assessment tools in AGS (Aim 1) by testing established functional outcomes tools and patient reported outcomes in this population including their responsiveness to baricitinib. We will further validate use of MRI-based metrics of brain morphometry and diffusion MRI that measure disease progression in AGS patients (Aim 2) across multiple testing centers, first harmonizing sequence acquisition and then determining the correlation of brain atrophy and white matter integrity with developmental outcomes in AGS. Finally, we will define context of use for tissue specific interferon biomarkers in AGS (Aim 3), by defining the relationship between measures of expression of interferon stimulatory genes (ISG) in blood, skin and clinical measures of neurologic function and skin disease. The proposed research will evaluate clinical outcomes tools for AGS clinical trials using patient-specific priorities and target key affected organs in the context of compassionate use of JAK inhibitors. It is expected that the development of these tools will allow appropriate design and implementation of clinical trials in AGS using JAK inhibitors and other interferon modulating therapies. Thus, we hope that this project, with urgent and unmet need in clinical trial readiness in a rare neurogenetic disease, will be viewed as responsive to PAR-18-534 and within the NINDS mission.