Available online 2 July 2022, 101633
AbstractThe eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3’s functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3’s relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.
AbbreviationsAMDage-related macular degeneration
A2EN-retinylidene-N-retinylethanolamine
CNVchoroidal neovascularization
DMEdiabetic macular edema
EFEMP-1EGF-containing fibulin-like extracellular matrix protein-1
EMAEuropean medicines agency
FDAfood and drug administration
IAPintegrin associated protein
iRORAincomplete RPE and outer retina atrophy
MACmembrane attack complex
MNVmacular neovascularization
mTORmammalian target of rapamycin
PDRproliferative diabetic retinopathy
POAGprimary open angle glaucoma
RPEretinal pigment epithelium
RVOretinal vein occlusion
SNPsingle nucleotide polymorphism
TSP-1thrombospondin – 1
VEGFvascular endothelial growth factor
KeywordsAge-related macular degeneration
Geographic atrophy
Complement
C3
Retina
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