Modulation of Macrophages and Complement Dysfunction in Nonexudative Age- Related Macular Degeneration Utilizing a Sialic-acid Coated Nanoparticle

Abstract

Purpose : Both the cellular and non-cellular components of the innate immune system are strongly implicated in the pathophysiology of age-related macular degeneration (AMD). Inhibition of the complement system has been shown to decrease the rate of progression of geographic atrophy in randomized clinical trials. We report a novel therapeutic strategy to address chronic inflammation in the retina by modifying the body’s own self-recognition system on immune cells. The therapeutic molecule AVD-104 (Aviceda Therapeutics, Cambridge, MA) is an engineered dual function glycan (sialic-acid) nanoparticle that directly modulates the self-pattern recognition receptors on immune cells called Siglecs (sialic-acid binding immunoglobulin-like lectins), thereby dampening the inflammatory activity of macrophages and microglia. The significant anti-inflammatory effect of AVD-104 has been previously confirmed in in-vitro experiments. Additionally, AVD-104 has been shown to enhance the activity of complement factor H and down-regulate the alternative complement cascade and has been shown to be safe in 3 species, including non-human primates.

Methods : AVD-104 was intravitreally (IVT) injected in humanized Siglec transgenic mice to assess efficacy in both the bright light damage (BLD) model of retinal degeneration (n=15 eyes) and the laser-induced model of choroidal neovascularization (CNV, n=21 eyes). In the BLD model, animals were given an IVT injection of AVD-104 one day before intense light exposure and examined 7 days later. In the laser CNV model, animals were given an IVT injection of AVD-104, lasered on the same day, and examined 8 days later.

Results : There was greater dose dependent preservation of the outer nuclear layer (p < 0.01) and reduction in Tumor Necrosis Factor-α levels (p < .0001) in the BLD animals treated with AVD-104 than controls. In the laser CNV mice, there was greater dose dependent reduction in the size of the CNV lesion and reduced C5b-9 complement deposition (Membrane attack complex) in AVD-104 treated eyes than controls.

Conclusions : Intravitreal injections of AVD-104, a novel sialic-acid coated nanoparticle have shown a statistically significant beneficial effect in reducing inflammatory retinal damage in two different animal models. A Phase 2 Human Clinical Trial for patients with AMD is planned for Q1’ 2023.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.