Exploring emerging JAK inhibitors in the treatment of Aicardi-Goutières syndrome.

Introduction: Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous monogenic autoinflammatory disorder classified as an 'interferonopathy'. Nine genes have been implicated in AGS, encoding proteins involved in nucleic acid clearance, repair, sensing, or histone pre-mRNA processing. Dysregulation in these pathways leads to excessive type I interferon production, the primary driver of the disease. AGS typically presents with early-life neurological regression, followed by stabilization with varying degrees of neurological impairment and common extra-neurological features, such as chilblains. Advances in understanding AGS pathogenesis have enabled the development of new therapies, with JAK inhibitors emerging as the most studied option for reducing interferon-mediated effects.

Areas covered: This review discusses the clinical features, genetic basis, and molecular pathways of AGS while tracing the evolution of its therapeutic strategies. Particular emphasis is placed on JAK inhibitors, which target proteins activated by type I interferons, providing a novel direction in treatment.

Expert opinion: Inhibitors effectively reduce extra-neurological symptoms in AGS, though their impact on neurological outcomes remains unclear. The unknown natural history of AGS limits treatment evaluation. Despite growing insights, key aspects of pathogenesis and treatment optimization - including timing, administration, and long-term effects - remain unresolved, highlighting the need for further research.