Poly Sialic-Acid Coated Nanoparticle attenuates Neovascularization, Inflammation and Complement Activity in AMD

Abstract

Purpose : Exudative (wet) age-related macular degeneration (AMD) is a progressive retinal inflammatory and degenerative disease resulting from abnormal blood vessel growth and leakage beneath the macula, leading to macular damage and blindness. In an in-vivo model for dry AMD, our previous research demonstrated the capacity of our Poly sialic-acid coated nanoparticle (PolySia-NP) to modulate macrophage-mediated inflammation by engaging with Siglec 11 (sialic-acid binding immunoglobulin-like lectins). To expand these findings to another pathology, we investigated the therapeutic effects of our PolySia-NP in a laser-induced choroidal neovascularization (CNV) mouse model, a well-established model for wet-AMD. Therefore, the purpose of this study was to assess the efficacy of our novel PolySia NP in attenuating the inflammatory response, neovascularization, and complement deposition by engaging with the humanized Siglec 11 receptor in transgenic mice.

Methods : Humanized Siglec-11 transgenic mice underwent Laser CNV following treatment with our PolySia-NP to characterize the efficacy of our drug. Eight days after laser CNV, the mice were euthanized, and the eyes were enucleated and fixed. To assess the extent of neovascularization and the microglia inflammatory response, choroidal flat-mounts were labeled with Isolectin-B4, Iba-1, and C5b-9 and assessed by microscopy. To further evaluate the inflammatory response following treatment with our PolySia-NP, TNFα ELISAs were performed on the homogenized retina, RPE/choroid/sclera, and vitreous humor samples.

Results : Our PolySia-NP, at 1.0mg/ml, significantly attenuated neovascularization (p<0.05), as shown by the decreased Isolectin-B4 staining. Furthermore, following treatment with 1.0 - 0.15mg/ml of our PolySia-NP, there was a significant reduction in microglial infiltration, phagocytic activity (p<0.05), and C5b-9 deposition. Lastly, there was a reduction in TNFα levels in the retina, RPE/choroid/sclera, and vitreous humor following treatment with our PolySia-NP.

Conclusions : Our PolySia-NP attenuated C5b-9 deposition, neovascularization, and inflammation by engaging with the humanized Siglec 11 receptor in transgenic mice. Our data supports the use of a novel engineered nanoparticle as a new potential approach for the treatment of exudative (wet) AMD patients by reducing the production of pro-inflammatory cytokines and neovascularization.

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