H-151, a Selective STING Inhibitor, Has Potential as a Treatment for Neovascular Age-Related Macular Degeneration

Purpose: The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) stimulator of interferon gene (STING) pathway is a crucial cascade in the inflammatory response initiated by the recognition of cytosolic double-stranded DNA (dsDNA). The aim of this study was to evaluate the effect of STING inhibitor in murine choroidal neovascularization (CNV). Methods: To investigate whether the cGAS–STING pathway is activated during CNV, CNV was induced using laser photocoagulation in male C57BL/6J mice. The expression of change of cGAS and STING during CNV development was confirmed by Western-blotting. H-151, a potent STING palmitoylation antagonist, was used as a STING inhibitor. H-151 was administered intravitreally immediately after laser induction. To confirm the role of the cGAS–STING pathway in CNV formation, we evaluated CNV size and performed fundus fluorescein angiography. Results: The expression levels of cGAS and STING were significantly upregulated in the RPE–choroid complex after CNV induction, and dsDNA merged with cGAS was observed in CNV lesions. Intravitreal administration of H-151 suppressed CNV development and fluorescent leakage from neovessels. In CNV lesions, the high expression of STING and cGAS was observed in infiltrating F4/80+ macrophages. H-151 administration attenuated downstream signals of the cGAS–STING pathway, including the phosphorylation of nuclear factor–κB, and downregulated the expression of interleukin 1β. Conclusions: These findings support that the inhibition of cGAS–STING pathway treats abnormal ocular angiogenesis.