THE PATHOPHYSIOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION AND THE COMPLEMENT PATHWAY AS A THERAPEUTIC TARGET

Abstract

Purpose: Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To date, there are no approved therapeutics for GA treatment; however, several are in clinical trials. This review focuses on the pathophysiology of GA, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade.

Methods: Primary literature search on PubMed for GA, complement cascade in age-related macular degeneration. ClinicalTrials.gov was searched for natural history studies in GA and clinical trials of drugs targeting the complement cascade for GA.

Results: Cumulative damage to the retina by aging, environmental stress, and other factors triggers inflammation via multiple pathways, including the complement cascade. When regulatory components in these pathways are compromised, as with several GA-linked genetic risk factors in the complement cascade, chronic inflammation can ultimately lead to the retinal cell death characteristic of GA. Complement inhibition has been identified as a key candidate for therapeutic intervention, and drugs targeting the complement pathway are currently in clinical trials.

Conclusion: The complement cascade is a strategic target for GA therapy. Further research, including on natural history and genetics, is crucial to expand the understanding of GA pathophysiology and identify effective therapeutic targets.

Fig. 1.

Multimodal imaging of geographic atrophy. Images of geographic atrophy (GA) from both eyes of one patient using color fundus photography (CFP), red-free imaging (RF), fluorescein angiography (FA), fundus autofluorescence (FAF), near-infrared fundus autofluorescence (NIR-FAF), and spectral domain optical coherence tomography (SD-OCT) (en face, cross-sectional, and macular cube images shown).

Fig. 2.

Impact of geographic atrophy progression on patient vision. As geographic atrophy (GA) progression usually begins outside of the fovea, decreasing the rate of GA area progression by 25% to 50% can potentially delay progression to the fovea by years, particularly if intervention is started early. Red: Natural progression; blue: 25% reduction; green: 50% reduction. A. GA progression over time; vertical reference lines note the time differences in atrophy progression to a given GA lesion size under these three scenarios. B. Illustration of GA area growth over time. Dotted circles represent expected GA growth per expected natural history (red) or with reduced speed of progression (blue, green). The rate of atrophy progression may be faster toward the periphery than toward the fovea. C. Example of progression of a GA lesion and its effect on patient vision. Central vision is largely preserved until atrophy encroaches on the fovea, though tasks requiring full-field vision, such as reading, can be impaired as peripheral vision is lost.

Fig. 3.

The complement cascade. CFB, complement factor B; CFD, complement factor D; CFH, complement factor H; CFI, complement factor I; CR1, complement receptor 1; DAF, decay accelerating factor; MAC, membrane attack complex; MASP, MBL-associated serine protease; MBL, mannose binding lectin; MCP, membrane cofactor protein.

Fig. 4.

Pathophysiology of geographic atrophy. Retinal layers: BM, Bruch's membrane; CC, choriocapillaris; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; MAC, membrane attack complex; ONL, outer nuclear layer; OPL, outer plexiform layer; PS, photoreceptor segment (inner and outer); RPE, retinal pigment epithelium.

Fig. 5.

Geographic atrophy (GA) therapeutics in development targeting the complement cascade. Several GA therapeutics (left) targeting different components of the complement cascade (center) are in Phase 2 or Phase 3 clinical trials. Also shown are factors such as the identified genetic variations (SNPs) that can affect complement cascade activity (right). CFB, complement factor B; CFD, complement factor D; CFH, complement factor H; CFI, complement factor I; MAC, membrane attack complex; SNP, single nucleotide polymorphism.