PolySia Nanoparticle Modulates M1 Macrophages Response Through Siglec Agonism as Mechanism of Action for Macular Degeneration Treatment

Abstract

Purpose : Age-related macular degeneration (AMD) is a progressive retinal disease which causes blindness in elderly. Studies indicate a prominent role of inflammation in the progression of AMD mediated by macrophages, particularly M1. The activation of macrophages in AMD is likely from oxidative products like cholesterol, phospholipids, and Low-Density Lipoprotein (OxLDL). Polysialic acid (PolySia)-nanoparticles (NPs) is a glycomimetic that has shown promising therapeutic potential for macular degeneration by dampening macrophage-mediated inflammation. The purpose of this study is to assess the Siglec and cytokine expression on M1 macrophages associated with AMD and demonstrate in vitro safety and effectiveness of PolySia nanoparticles to modulate OxLDL-activated macrophages response

Methods : We analyzed RNAseq GSE135092 dataset for Siglec-7, -9 and -11, TNF-α and IL-6 cytokine expression on M1 macrophages from AMD retinas and compared to normal controls. Next, we evaluate toxicity on PBMC-derived M1 macrophages treated with PolySia-NP for 18hr and assessed by CytoTox96 toxicity assay. Then, we determined TNF-α released on PBMC-derived M1 macrophages treated with PolySia-NPs or sucrose as control, and using Low-Density Lipoprotein from Human Plasma, oxidized (OxLDL) as stimulant. TNF-α released to the supernatant were measured 24 hours post treatment by ELISA assay

Results : AMD patients showed high correlation (R) of Siglec-7, -9 and -11 expression in M1 macrophages with an increased correlation of TNF-α and IL-6 compared to control group. No toxicity was observed at any tested concentration of PolySia-NPs compared to untreated control. TNF-α production showed dose depending inhibitory effect of PolySia-NPs in M1 macrophages in presence of OxLDL compared to sucrose control.

Conclusions : Our finding shows that Siglecs-7, -9 and -11 are upregulated on M1 macrophages with increased TNF-α and IL-6, suggesting a crucial role in AMD. The PolySia-NPs targeting Siglec significantly suppress macrophage functions by reducing production of pro-inflammatory cytokines without cytotoxic effects. Our data supports the use of PolySia-NPs for AMD treatment by reducing pro-inflammatory macrophage response through Siglecs agonism on M1 macrophages

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.