Abstract
Neovascular age-related macular degeneration (nAMD) is a major cause of blindness and is characterized by pathologic angiogenesis, specifically choroidal neovascularization (CNV). Mononuclear phagocytes (MPs), including infiltrating systemic monocyte-derived macrophages and retinal microglia, play critical roles in promoting CNV. The cGAS/STING pathway is increasingly implicated in multiple neuronal and systemic diseases and recently in ocular neovascularization. Given its roles across multiple cell types and the absence of MP-targeted therapies, we investigated the MP-specific role of cGAS/STING and a strategy for its selective targeting. In the laser-induced CNV mouse model, cGAS/STING was predominantly expressed in MPs. To enable selective targeting, we used a hydroxyl dendrimer (HD) previously shown to target MPs. HD conjugated to Cy3 selectively localized to MPs in laser CNV. HD conjugated to the STING inhibitor SN-011 (HD-SN-011) effectively inhibited cGAS/STING activation in cultured MPs. In the laser-CNV model, HD-SN-011 significantly reduced CNV leakage and lesion size, both important clinical endpoints in nAMD. RiboTag profiling confirmed selective suppression of cGAS/STING signaling and inflammatory gene expression in MPs. Together, our results implicate the specific importance of MP cGAS/STING signaling in CNV and provide proof of concept for specific modulation of STING in MPs as a therapy for nAMD.
Authors
Le Shi, Durgadas Cherukaraveedu, Hongkwan Cho, Kaoru Ri, Lingli Zhou, Yingxue Cao, Narendra Kale, Zhenhua Xu, Wathsala Liyanage, Rangaramanujam M. Kannan, Elia J. Duh
Figure 2
Synthesis and characterization of HD-SN-011 with improved solubility and physicochemical stability.
