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

• Published in: Investigative Ophthalmology & Visual Science Vol. 65; no. 8; p. 16
• Main Authors: Tanaka, Miruto, Yasuda, Hiroto, Nakamura, Shinsuke, Shimazawa, Masamitsu
• Format: Journal Article
• Language: English
• Published: United States Association for Research in Vision and Ophthalmology (ARVO) 09.07.2024; The Association for Research in Vision and Ophthalmology
• Subjects: Animals; Blotting, Western; Choroid - metabolism; Choroid - pathology; Choroidal Neovascularization - drug therapy; Choroidal Neovascularization - metabolism; Disease Models, Animal; Fluorescein Angiography; Intravitreal Injections; Macular Degeneration - drug therapy; Macular Degeneration - metabolism; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Nucleotidyltransferases - antagonists & inhibitors; Nucleotidyltransferases - metabolism; Retina
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.65.8.16

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). 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. 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. These findings support that the inhibition of cGAS-STING pathway treats abnormal ocular angiogenesis.