The role of the complement system in age-related macular degeneration

Abstract

Background: Age-related macular degeneration (AMD) is a common retinal disease in older people. In Europe, about 1.6% of persons over age 65 and more than 13% of persons over age 85 have late-stage AMD, which can severely impair vision. The development of AMD is influenced both by environmental factors and by a strong hereditary component.

Method: We selectively searched the PubMed database for articles published between April 2001 and November 2013 with the key words "age-related macular degeneration," "risk factor," "complement," and "therapy." The website www.clinicaltrials.gov was also used to search for relevant clinical trials.

Results: Old age and smoking are confirmed risk factors for AMD. Moreover, genetic association studies have pointed to signaling pathways in which the complement system, a part of the individual's innate immune system, takes on a central role in the pathogenesis of the disease. Several clinical trials designed to interfere specifically with these pathomechanisms have yielded rather disappointing results, although a phase II study of the monoclonal antibody lampalizumab showed that blocking complement factor D lessened the progression of geographic atrophy. A risk model based on 13 genetic markers was found to have positive predictive values in predisposed individuals that ranged from 5.1% (in persons aged 65 to 69) to 91.7% (in persons aged 85 or older). It should be borne in mind that 50% of patients with AMD are not carriers of risk-associated markers.

Conclusion: There is no rationale at present for genetic testing to estimate the individual risk of developing AMD. Several recent clinical trials have incorporated current pathophysiological knowledge, but nearly all of these trials have yielded negative findings, with only one exception.

Figure 1

Clinical manifestation of age-related macular degeneration. Imaging of the ocular fundus (left) and high-resolution optical coherence tomography (OCT) (right) of (a) early and (b, c) late AMD (b: geographic atrophy [GA], c: choroidal neovascularization [CNV]). The dashed line indicates the location of the OCT section. 1 = photoreceptor layer, 2 = retinal pigment epithelium (RPE). (a) Ocular fundus imaging shows multiple drusen on the fundus (yellowish deposits beneath the RPE at Bruch’s membrane), the typical manifestation of early dry AMD. OCT reveals drusen as deposits beneath the RPE (= 3). (b) The arrows indicate a central area of sharply delineated atrophy with loss of RPE and photoreceptor cells; this is also shown on the OCT (= 4). This atrophying is accompanied by complete loss of function in the affected area. (c) The final stage of neovascular AMD is subretinal scarring with degeneration of photoreceptors, RPE, and choroid membrane in the affected area. No retinal function is preserved in scarred areas.

eFigure

Complement system and modulating drugs, preclinically and clinically. Drugs used to treat age-related macular degeneration (AMD) can be divided into three complement system activation pathways but also target the unifying, final enzyme complexes. Activation occurs via the classical (yellow, orange), lectin-dependent (red, orange), and alternative (blue, purple) pathways. The central stages (gray) involve enzyme complexes (convertases) that cleave C3 and C5. The final common pathway of the complement cascade leads to the formation of a terminal membrane attack complex in the cell (C5b-9), circulating anaphylatoxins (C3a, C5a), and opsonin (C3b). Complement regulators such as complement factor H (CFH) and complement factor I (CFI) prevent uncontrolled feedback loops. Complement components that are genetically associated with AMD are shown in bold and underlined. Target proteins for which treatments are being developed have been labelled using superscript figures that indicate further information on the drugs concerned (corresponding to the numbering in the Table [Text] and eTable 2). MBL: mannan-binding lectin; MASP: MBL-associated serine protease; FD: factor D; FB: factor B; P: properdin; CFH: complement factor H; CFI: complement factor I (Figure modified according to Khandhadia et al. [39])