The Complement System as a Therapeutic Target in Retinal Disease

Abstract

The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.

Keywords: age-related macular degeneration; choroid; complement system; retinal therapy.

Figure 1

Overview of the complement cascade involving the classical, lectin, and alternative pathways to construct the membrane attack complex. Anaphylatoxins (C3a, C4a, and C5a) may trigger inflammatory responses, while regulatory proteins CFH and C59 may modulate the activity of the complement system.

Figure 2

Complement activation in geographic atrophy. The deterioration of retinal pigment epithelium (RPE) in geographic atrophy (GA) allows for additional complement to access the retina. Complement activation leads to the formation of the membrane attack complex, thus leading to destruction and cell death of photoreceptors and RPE in GA. Figure reprinted with permission from Campagne et al. [41] under Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/legalcode.en, accessed on 1 March 2024).

Figure 3

Pathologic changes that precede age-related macular degeneration (AMD). The green section indicates that healthy eyes without CFH Y402H mutations can freely regulate transport of oxygen and other nutrients from the choroidal circulation (circulation) through the blood-retinal barrier and to the RPE and photoreceptors. In eyes with this CFH Y402H mutation, there is a predisposition for AMD (yellow section). The RPE cells exhibit decreased oxidative phosphorylation (ox phos) capacity. In conjunction with natural aging, there is a disruption in transport through the Bruch membrane. Unchecked complement activation occurs depending on the severity of the mutations and the degree of extracellular matrix (ECM) disruption. Oxidative stress induces RPE cell damage, further promoting a pro-inflammatory state by causing cytokine release (IL-6, IL-8). In early stage AMD (red), there is an accumulation of oxidized lipoproteins (drusen) that form in the Bruch membrane. There are degenerative changes in macular RPE cells and photoreceptors. Figure reprinted with permission from Armento et al. [48] under Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/legalcode.en, accessed on 1 March 2024).

Figure 4

Natural aging and the progression to late-stage AMD. This figure demonstrates the key stages of AMD progression, beginning with an overview of ocular anatomy (A,B), natural aging processes (C), early/intermediate AMD (D), late-stage non-exudative (dry) AMD (E), and finally late-stage exudative (wet) AMD (F). In natural aging, changes in the Bruch membrane (C) impair the exchange of nutrients for waste, damaging local structures such as the RPE. Inflammatory processes take hold, and the complement system is activated (D). In late-stage disease, there is either widespread RPE atrophy (geographic atrophy) (E) or else CNV network formation (F). Figure reprinted with permission from Armento et al. [48] under Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/legalcode.en, accessed on 1 March 2024).

Figure 5

Geographic atrophy visualized using different imaging modalities. Box (A) demonstrates multicolor imaging showing reflectance in different wavelengths in geographic atrophy. Box (B) demonstrates fundus autofluorescence, showing geographic atrophy as sharply demarcated dark regions. Box (C) shows infrared reflectance with an adjacent optical coherence tomography (OCT) B-scan of the central fovea, showing the loss of outer retinal layers and retinal pigment epithelium. Box (D) demonstrates en face OCT angiography, showing loss of flow at the choriocapillaris within the lesion. Box (E) demonstrates en face OCT, showing hyper-reflectance at the choriocapillaris layer due to backscattering. Box (F) demonstrates an OCT angiography B-scan of the central fovea showing loss of flow in the choriocapillaris. Reprinted with permission from Sacconi et al. [163] under Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/legalcode.en, accessed on 1 March 2024).