Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD. The aim of this review is to (i) reflect on the possible complement targets in the context of wAMD pathology, (ii) investigate the results of prior clinical trials with complement inhibitors for wAMD patients, and (iii) outline important considerations when developing a future strategy for the treatment of wAMD.

Genetic Variants of Complement Factor H Y402H (rs1061170), C2 R102G (rs2230199), and C3 E318D (rs9332739) and Response to Intravitreal Anti-VEGF Treatment in Patients with Exudative Age-Related Macular Degeneration

“…This leads to the development of chronic local inflammation (parainflammation or inflammaging), resulting in macular lesions [ 33 , 50 ]. Throughout life, the retina is subject to oxidative damage, which affects the expression of complement components in the aging retina and AMD-diseased tissues [ 62 , 63 , 64 , 65 , 66 ]. The oxidized photoreceptor outer segment material was shown to reduce the synthesis of complement factor H in cultured RPE cells [ 61 ].…”

Human immune system adaptations to simulated microgravity revealed by single-cell mass cytometry

“…Unarguably, spaceflight is the ideal environment for studying immune cell function in μG. However, sμG experiments using validated models, such as the RWV, the two-dimensional clinorotation or the RPM models 9 , 27 – 31 , are an important experimental paradigm for the cost-effective discovery of novel biology that can then be tested in confirmatory in-flight experiments. Importantly, we have compared previous data from spaceflight and sμG of the rotating wall vessel and random positioning machine and have found that expression of measured transcripts (including IL2Rα, TNFα, CD69, and CCL4) was consistent between different sμG models and between sμG and spaceflight 9 , 12 , 14 , 39 .…”

“…Here, we utilized a 41-parameter mass cytometry approach to comprehensively profile the effect of µG on human PBMC surface activation markers and intracellular signaling responses, cultured in the NASA developed Rotating Wall Vessel, one of the most commonly used models of simulated (s)µG 25 , 26 . Other established sµG models include the two-dimensional clinorotation and the Random Positioning Machine models 9 , 27 – 31 . The primary goal of the study was to expand current knowledge anchored in bulk transcriptomic profiles of PBMCs 4 , 12 , 14 , 15 by adding a single-cell and proteomic readout of major immune cell effector function after exposure to sµG.…”

Publication Trends of Research on Polypoidal Choroidal Vasculopathy During 2001–2020: A 20-Year Bibliometric Study

“…The activated complement system aggravates inflammation, form membrane-attack complex (MAC), induces tissue damage and neovascularization ( 44 ). In recent years, anti-complement therapy combined with anti-VEGF has been practiced in many clinical trials ( 45 ). Two clinical trials, which are pegcetacoplan (selective C3 inhibitor) and avacincaptad pegol (C5 inhibitor), have reduced the 29 and 27.4% rate of geographic atrophy (GA) leison enlargement ( 46 ).…”