Mononuclear phagocyte-specific cGAS/STING targeting suppresses experimental choroidal neovascularization

Area of Science:

• Ophthalmology
• Immunology
• Molecular Biology

Background:

• Neovascular age-related macular degeneration (nAMD) causes blindness via choroidal neovascularization (CNV).
• Mononuclear phagocytes (MPs), including macrophages and microglia, are key drivers of CNV.
• The cGAS/STING pathway is implicated in various diseases, including recent findings in ocular neovascularization.

Purpose of the Study:

• To investigate the role of the cGAS/STING pathway specifically within MPs in CNV.
• To develop a targeted therapeutic strategy for inhibiting MP cGAS/STING signaling in nAMD.

Main Methods:

• Utilized a laser-induced CNV mouse model.
• Employed a hydroxyl dendrimer (HD) for selective MP targeting.
• Developed an HD-conjugated STING inhibitor (HD-SN-011) to block cGAS/STING activation in MPs.
• Assessed CNV leakage, lesion size, and MP inflammatory gene expression.

Main Results:

• cGAS/STING was predominantly expressed in MPs within the CNV model.
• HD-SN-011 selectively targeted MPs and inhibited cGAS/STING activation.
• HD-SN-011 significantly reduced CNV leakage and lesion size.
• Selective suppression of cGAS/STING signaling and inflammatory genes in MPs was confirmed.

Conclusions:

• MP-specific cGAS/STING signaling is crucial for the development of CNV.
• Targeted inhibition of STING in MPs presents a promising therapeutic approach for nAMD.
• This study provides proof of concept for MP-specific STING modulation as an nAMD therapy.