Link to Pubmed [PMID] – 28426911
2017 Apr;
OBJECTIVE: Gain-of-function mutations in TMEM173 encoding STING (stimulator of interferon genes) underlie a novel type I interferonopathy, minimally responsive to conventional immunosuppressive therapies and associated with high childhood morbidity and mortality. STING gain-of-function causes constitutive over secretion of interferon (IFN). We determined the effects of a TBK1/IKKE inhibitor (BX795) on IFN secretion and signaling in primary peripheral blood mononuclear cells (PBMCs) from four patients.
METHODS: PBMCs from STING patients were treated with BX795. The effect of BX795 on IFN pathways was assessed by western blot, an IFNβ reporter assay, IFNα quantification in cell lysates, STAT1 phosphorylation status and by RNA expression of IFN-stimulated genes (ISGs).
RESULTS: BX795 inhibited the phosphorylation of IRF3 and IFNβ promoter activity induced in HEKs by cGAMP or by genetic activation of STING. In vitro exposure to BX795 inhibited IFNα production in PBMCs of STING-mutated patients without affecting cell survival. In addition, BX795 decreased STAT1 phosphorylation and ISG expression independently of IFNα blockade.
CONCLUSIONS: Our findings demonstrate the effect of BX795 on reducing type I IFN production and IFN signaling in cells from patients with gain-of-function mutations in STING. A combined inhibition of TBK1 and IKKΕ therefore holds potential for the treatment of STING-mutated patients, and may also be relevant in other type I interferonopathies. This article is protected by copyright. All rights reserved.