Complement System and Potential Therapeutics in Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system.

Keywords: age-related macular degeneration; clinical trial; complement cascade; therapeutics.

Figure 1

(A) Anatomy of the fundus and macula (circle) in a normal eye. (B,C) Layer-by-layer B-scan swept-source optical coherence tomography display of normal retina. CC, choriocapillaris; ELM, external limiting membrane; GCL, ganglion cell layer; ILM, inner limiting membrane; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; PR, photoreceptor; RPE, retinal pigment epithelium.

Figure 2

Clinical image of age-related macular degeneration (AMD). Color fundus photograph, red-free fundus photograph and swept-source optical coherence tomography (SS-OCT) images showing the characteristics of early and intermediate AMD (A,B), neovascular AMD (C) and geographic atrophy (D). (A,B) Non-neovascular AMD: Images showing small and intermediate soft drusen. (C) Neovascular AMD: subretinal fluid with subfoveal hemorrhage and a large pigment epithelial detachment. (D) Geographic atrophy: a well-demarcated area of fovea-involving retinal pigment epithelium atrophy.

Figure 3

The complement cascade. MBL, mannose-binding lectin; MASP, MBL-associated serine protease; CFB, complement factor B; CFD, complement factor D.

Figure 4

Schematic representation of the pathogenesis from early to late stages of age-related macular degeneration (AMD). CFH, complement factor H; CFI, complement factor I; CNV, choroidal neovascularization; GA, geographic atrophy; RPE, retinal pigmented epithelium; VEGF, vascular endothelial growth factor.