Abstract Objectives Aicardi–Goutières syndrome (AGS) is a rare genetic interferonopathy because of aberrant DNA or RNA metabolism that lacks effective disease modifying therapies. Methods Single‐cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) obtained from a patient with AGS because of pathogenic biallelic SAMHD1 variants to assess baseline gene dysregulation compared to an age‐ and sex‐matched control. The patient and control's PBMCs were incubated with the novel clinical stage cGAS inhibitor IMSB301 for 24 h, followed by evaluation of its effects on in vitro gene expression. Results In PBMCs from the patient with SAMHD1 mutation, at baseline, the most upregulated enriched pathways were ‘response to virus’ and ‘response to type 1 interferon’; these were also the most downregulated pathways after in vitro IMSB301 treatment. The top five most upregulated genes at baseline were interferon‐stimulated genes (ISG) IFIT1, IFIT3, IFI44L, ISG15, OAS1 , which were downregulated to control levels after in vitro treatment with IMSB301. Conclusion The cGAS inhibitor IMSB301 resulted in specific reduction in interferon signalling in vitro in PBMCs from a patient with SAMHD1 mutation, indicating a potential therapeutic role in genetic interferonopathy.
Han et al. (Sun,) studied this question.