International Journal of Molecular Sciences Review Complement System and Potential Therapeutics in Age-Related Macular Degeneration Young Gun Park 1, Yong Soo Park 2 and In-Beom Kim 2,3,4,* 1 Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; [email protected] 2 Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; [email protected] 3 Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea 4 Catholic Institute for Applied Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea * Correspondence: [email protected]; Tel.: +82-2-2258-7263 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. Citation: Park, Y.-G.; Park, Y.-S.; Kim, I.-B. Complement System and Keywords: age-related macular degeneration; complement cascade; clinical trial; therapeutics Potential Therapeutics in Age-Related Macular Degeneration. Int. J. Mol. Sci. 2021, 22, 6851. https://doi.org/ 10.3390/ijms22136851 1. Introduction Age-related macular degeneration (AMD) is a leading cause of vision loss in elderly Academic Editor: Janusz Blasiak people in developed countries [1–3]. It is related to various risk factors and genetic predis- positions for a number of patients [4]. In 2020, the AMD prevalence rate was 196 million, Received: 30 April 2021 and this is projected to increase to up to 288 million in 2040 [5]. Irreversible central vision Accepted: 23 June 2021 Published: 25 June 2021 loss has devastating effects on the physical, social, and emotional aspects of the patients and leads to a high societal cost burden. However, the treatment options targeting vascular leakage are available only for Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in patients with the neovascular form of the disease. Importantly, no precise curative treat- published maps and institutional affil- ment modality has been developed despite treatment advances for this disease. The most iations. important aspects are modifiable risk factors and routine ophthalmic monitoring. This limitation of effective therapeutic options is also likely due to incomplete knowledge of the mechanisms involved in AMD pathogenesis. There is a lack of updated and concise papers focused on the complement system cas- cades associated with the pathogenesis of AMD, although there have been much research Copyright: © 2021 by the authors. and many review articles [6–9]. In this review, we aim to provide a concise mini-review on Licensee MDPI, Basel, Switzerland. This article is an open access article how these pathways are affected in AMD progression and the key factors for the potential distributed under the terms and therapeutics in AMD. conditions of the Creative Commons 2. Clinical Classification of AMD Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ The center of the retina is the macula, and it can be divided into six parts: the umbo, 4.0/). foveolar, foveal avascular zone, fovea, parafovea, and perifoveal areas. Among them, the Int. J. Mol. Sci. 2021, 22, 6851. https://doi.org/10.3390/ijms22136851 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 18 Int. J. Mol. Sci. 2021, 22, 6851 2 of 15 2. Clinical Classification of AMD The center of the retina is the macula, and it can be divided into six parts: the umbo, foveafoveolar, is a tiny foveal pit avascular which is zone, located fovea, at theparafovea, center and of the perifoveal macula areas. and Among contains them, the the largest concentrationsfovea is a tiny of cones,pit which which is located are responsible at the center for of central the macula vision and with contains high resolution. the largest The retinaconcentrations is composed of ofcones, ten layers,which are from responsible the anterior for central to posterior: vision w innerith high limiting resolution. membrane, The nerveretina fiber is layer,composed ganglion of ten cell layers layer,, from inner the plexiformanterior to layer,posterior: inner inner nuclear limiting layer, membrane, outer plexi- nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plex- form layer, outer nuclear layer, external limiting membrane, rods and cones (photoreceptor) iform layer, outer nuclear layer, external limiting membrane, rods and cones (photorecep- and retinal pigment epithelium (RPE). Bruch’s membrane (BM) is attached to the basal tor) and retinal pigment epithelium (RPE). Bruch’s membrane (BM) is attached to the basal surfacesurface of the of the RPE, RPE, and and the the choriocapillaris choriocapillaris is is adjacent adjacent toto BMBM (Figure(Figure 11).). However, close close to the fovealto the foveal pit, the pit, layers the layers between betw theeen ganglionthe ganglion cell cell layer layer and and inner inner nuclear nuclear layer layer abruptly ab- becomeruptly thinner become and thinner finally and disappear, finally disappear, while thewhile layers the layers between between the the outer outer plexiform plexiform layer andlayer RPE and remain, RPE andremain, thus, and fovea thus, isfovea composed is composed of a few of a layers,few layers including, including a very a very thin thin inner plexiforminner plexiform layer, the layer, outer the nuclear outer nuclear layer, thelayer, cones, the cones, and the and RPE the RPE layers. layers. FigureFigure 1. (A) Anatomy1. (A) Anatomy of the of fundus the fundus and and macula macula (circle) (circle) in in a a normal normal eye.eye. (B,C)) Layer Layer-by-layer-by-layer B- B-scanscan swept swept-source-source optical optical coherence tomography display of normal retina. CC, choriocapillaris; ELM, external limiting membrane; GCL, ganglion coherencecell tomographylayer; ILM, inner display limiting of normalmembrane; retina. INL, CC, inner choriocapillaris; nuclear layer; IPL, ELM, inner external plexiform limiting layer; membrane;NFL, nerve fiber GCL, layer; ganglion ONL, cell layer; ILM,outer innernuclear limiting layer; OPL, membrane; outer plexiform INL, inner layer; nuclear PR, photoreceptor; layer; IPL, RPE, inner retinal plexiform pigment layer; epithelium. NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; PR, photoreceptor; RPE, retinal pigment epithelium. AMD is a degenerative disease of the retina that leads to changes in photoreceptors, RPE,AMD BM, is aand/or degenerative choriocapillaris, disease eventually of the retina resulting that leadsin central to changes visual impairment in photoreceptors, [10]. RPE,The BM, pathology and/or of choriocapillaris, AMD is characterized eventually by macular resulting drusen, in centralRPE atrophy, visual choroidal impairment neo- [10]. Thevascularization pathology of AMD(CNV), is neurosensory characterized retinal by macular detachment, drusen, and RPEdisciform atrophy, scars choroidal or lesions.neo- vascularizationThe hallmark (CNV), of AMD neurosensory is drusen, extracellular retinal detachment, debris that accumulate and disciforms with scars age, orin lesions.the Thearea hallmark below of the AMD RPE, is and drusen, consist extracellulars of cellular debrisdebris, thatlipoproteins, accumulates and amyloid with age, deposits. in the area belowThis the may RPE, lead and to impaired consists ofRPE cellular function debris, and disruption lipoproteins, of the and metabolic amyloid transport deposits. be- This maytween lead toRPE impaired and choroid RPE [11]. function and disruption of the metabolic transport between RPE Simplified classification scales according to the clinical features for AMD have been and choroid [11]. developed. The Age-related Eye Disease Study (AREDS) research group classified pa- Simplified classification scales according to the clinical features for AMD have been tients into four categories according to the size and extent of drusen, presence of geo- developed. The Age-related Eye Disease Study (AREDS) research group classified patients into four categories according to the size and extent of drusen, presence of geographic atrophy (GA), and neovascular changes [12,13]. Currently, simplified classification scales according to the clinical features for AMD have been developed and have become widely used (Table1)[14]. AMD is categorized into three clinical stages: early, intermediate, and late-stage AMD [14]. Early stage AMD is characterized by the presence of medium-sized drusen (>63 and ≤125 µm) without any impairment of visual function. Intermediate-stage AMD is defined as the presence