TBK1 / IKKE blockade inhibits mutant STING mediated inflammatory response in patient cells

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 IFN reporter assay, IFN quantification in cell lysates, STAT1 phosphorylation status and by RNA expression of IFN-stimulated genes (ISGs).
Results: BX795 inhibited the phosphorylation of IRF3 and IFN promoter activity induced in HEKs by cGAMP or by genetic activation of STING. In vitro exposure to BX795 inhibited IFN production in PBMCs of STING-mutated patients without affecting cell survival. In addition, BX795 decreased STAT1 phosphorylation and ISG expression independently of IFN 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 IKK therefore holds potential for the treatment of STING-mutated patients, and may also be relevant in other type I interferonopathies.