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GA and the Complement System

Understanding the Complement System Is Critical to Addressing GA3

In GA, excessive activity of the complement system increases inflammation and triggers phagocytosis and cell death of the retinal pigment epithelium (RPE).3

C3 convertase

All 3 complement pathways (classical, lectin, and alternative) converge at the C3 convertase enzyme1

C3

C3 convertase cleaves C3 to form C3a and C3b. C3a has proinflammatory effects through inflammasome activation

C3b plays a role in pathogen opsonization and may be beneficial for anti-inflammatory activities1,2,4

C5 convertase

As C5 convertase cleaves C5 into C5a and C5b, it initiates the terminal cascade of the complement system1

C5

C5 initiates the terminal step of the complement system5

C5a

Can lead to inflammation that causes the death of RPE cells1,6

C5b

Initiates cell death through the membrane attack complex (MAC)7

The role of the complement system has emerged as a research target for the treatment of GA.1,2

References:

  1. Boyer DS, Schmidt-Erfuth U, van Lookeren Campagne M, Henry EC, Brittain C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835.

  3. Xu H, Chen M. Targeting the complement system for the management of retinal inflammatory and degenerative diseases. Eur J Pharmacol. 2016;787:94-104.

  5. Bakri SJ, Bektas M, Sharp D, et al. Geographic atrophy: mechanism of disease, pathophysiology, and role of the complement system. J Manag Care Spec Pharm. 2023;29(5-aSuppl):S2-S11.

  7. Coulthard LG, Woodruff TM. Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol. 2015;194(8):3542-3548.

  9. Danzig CJ, Khanani AM, Loewenstein A. C5 inhibitor avacincaptad pegol treatment for geographic atrophy: a comprehensive review. Immunotherapy. 2024;16(12):779-790.

  11. Brandstetter C, Holz FG, Krohne TU. Complement component C5a primes retinal pigment epithelial cells for inflammasome activation by lipofuscin-mediated photooxidative damage. J Biol Chem. 2015;290(52):31189-31198.

  13. Kumar-Singh R. The role of complement membrane attack complex in dry and wet AMD - from hypothesis to clinical trials. Exp Eye Res. 2019;184:266-277.