Efficacy of Complement C3 Inhibition in Preclinical Models of Wet Age-related Macular Degeneration (AMD)

Abstract

Purpose : Several lines of evidence, including human genetics, animal models, and recent clinical trial results, implicate complement system dysregulation in the pathogenesis of AMD. Published preclinical studies demonstrated the potential benefit of complement inhibition, at various points in the pathway, in rodent models of neovascular AMD. However, despite the central role of complement factor C3 (C3) in the activation of complement cascade, pharmacological intervention to inhibit C3 in these models remains largely unexplored. The goal of this study was to examine the effects of pharmacological and genetic inhibition of C3 in a rodent choroidal neovascularization (CNV) model.

Methods : We used an image-guided laser-induced CNV model in C57BL/6 wild type and C3^-/- mice (JAX Stock #32042, backcrossed to C57BL/6 mice). Pharmacological inhibition of C3 was achieved by intravitreal (IVT) administration of an inhibitory anti-mouse C3 antibody one day prior to laser treatment. Seven days after laser was used to rupture Bruch’s membrane and induce CNV, vascular leakage was quantified by fluorescein angiography (FA) and CNV lesion size measured in eyecup flat-mounts stained with isolectin B4.

Results : Genetic ablation and pharmacological inhibition of C3 resulted in improved phenotypes in laser-induced CNV models. Specifically, CNV leakage was reduced by 52% in C3^-/- mice compared to wild-type control mice. Comparable results (38% reduction) were achieved with a single IVT injection of an anti-C3 inhibitory antibody. Reduction in CNV lesion size failed to reach statistical significance in these studies.

Conclusions : We demonstrate that C3 deficiency/inhibition reduces vascular leakage in the rodent laser-induced CNV model, suggesting the therapeutic potential for C3 inhibition for neovascular AMD. We continue to investigate the mechanism through which complement inhibition affects the progression of angiogenesis in response to acute injury.

This is a 2020 ARVO Annual Meeting abstract.