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.

Methods: We report on two patients diagnosed with AGS due to biallelic mutations in RNASEH2B who presented with dystonia, spastic tetraparesis, microcephaly, and global developmental delay. Patients were treated with the JAK inhibitor ruxolitinib since the age of 23 months.

Results: Ruxolitinib, given for 8 and 13 months, respectively, is so far well tolerated by both patients without any signs of myelosuppression. Both patients responded with a marked reduction in ISG expression. During periods of common infections of the upper respiratory tract transient increases in ISG expression were noted. While a developmental progress is registered regarding exploratory behavior, feeding skills and decline of dystonic movements, it cannot be conclusively attributed to ruxolitinib alone.

Conclusion: These findings suggest a possible benefit of type I IFN suppression through JAK inhibition using ruxolitinib in children with AGS. However, further clinical studies are necessary to evaluate the clinical efficacy.

No conflict of interest has been declared by the author(s).