Research progress on the complement system in wet age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Guina ^1,2 , Jiang Xiaoshuang ¹ , Yang Tingting ¹ ,  Lu Fang ¹

1. Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China;
2. Department of Ophthalmology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China;

Corresponding author：

Lu Fang, Email: lufang@wchscu.cn

Keywords：

Complement system; Wet age-related macular degeneration; Choroidal neovascularization; Complement inhibitors; Review

DOI：

10.3760/cma.j.cn511434-20250220-00062

Video：

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Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness worldwide. Wet AMD (wAMD) is the primary type of AMD leading to blindness, characterized by rapid vision loss due to neovascularization. Currently, the primary treatment for wAMD relies on anti-vascular endothelial growth factor (VEGF) drugs. However, some patients respond poorly to this therapy, suggesting a complex pathogenesis that necessitates the exploration of multi-target therapeutic strategies. Recent studies have revealed that aberrant activation of the complement system plays a crucial role in the development of wAMD. Specifically, molecules such as C3, C5, C3a, C5a, and the membrane attack complex (MAC) are involved in the formation of choroidal neovascularization (CNV) by modulating VEGF and other inflammatory factors. Genetic studies have confirmed a strong association between mutations in complement-related genes and wAMD, such as CFH and C3. Furthermore, animal experiments support the therapeutic potential of complement inhibitors in treating CNV. Currently, clinical trials targeting complement components like C3, C5, and MAC are underway, with some drugs having advanced to phase II/III clinical studies. However, their efficacy requires further validation. In the future, complement-targeted therapy, particularly in combination with anti-VEGF treatment, is poised to become a new direction in wAMD management, potentially offering superior therapeutic options for patients.

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1. Han X, Gharahkhani P, Mitchell P, et al. Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration[J]. J Hum Genet, 2020, 65(8): 657-665. DOI: 10.1038/s10038-020-0750-x.
2. Ye H, Zhang Q, Liu X, et al. Prevalence of age-related macular degeneration in an elderly urban chinese population in China: the Jiangning Eye Study[J]. Invest Ophthalmol Vis Sci, 2014, 55(10): 6374-6380. DOI: 10.1167/iovs.14-14899.
3. Song P, Du Y, Chan KY, et al. The national and subnational prevalence and burden of age-related macular degeneration in China[J/OL]. J Glob Health, 2017, 7(2): 020703[2017-12-01]. https://pubmed.ncbi.nlm.nih.gov/29302323/. DOI: 10.7189/jogh.07.020703.
4. 中华医学会眼科学分会眼底病学组, 中国医师协会眼科医师分会眼底病学组. 中国年龄相关性黄斑变性临床诊疗指南(2023年)[J]. 中华眼科杂志, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.Retinal Disease Group, Ophthalmology Branch of Chinese Medical Association, Retinal Disease Group, Ophthalmology Branch of Chinese Medical Doctor Association. Evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China (2023)[J]. Chin J Ophthalmol, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.
5. Sarks S, Cherepanoff S, Killingsworth M, et al. Relationship of Basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2007, 48(3): 968-977. DOI: 10.1167/iovs.06-0443.
6. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern^®[J]. Ophthalmology, 2020, 127(1): 1-65. DOI: 10.1016/j.ophtha.2019.09.024.
7. Mettu PS, Allingham MJ, Cousins SW. Incomplete response to Anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities[J/OL]. Prog Retin Eye Res, 2021, 82: 100906[2021-10-03]. https://pubmed.ncbi.nlm.nih.gov/33022379/. DOI: 10.1016/j.preteyeres.2020.100906.
8. Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration[J]. Med Clin North Am, 2021, 105(3): 473-491. DOI: 10.1016/j.mcna.2021.01.003.
9. Spaide RF, Jaffe GJ, Sarraf D, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data: consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group[J]. Ophthalmology, 2020, 127(5): 616-636. DOI: 10.1016/j.ophtha.2019.11.004.
10. Elsheikh RH, Chauhan MZ, Sallam AB. Current and novel therapeutic approaches for treatment of neovascular age-related macular degeneration[J/OL]. Biomolecules, 2022, 12(11): 1629[2022-11-03]. https://pubmed.ncbi.nlm.nih.gov/36358978/. DOI: 10.3390/biom12111629.
11. Rastoin O, Pagès G, Dufies M. Experimental models in neovascular age related macular degeneration[J/OL]. Int J Mol Sci, 2020, 21(13): 4627[2020-06-29]. https://pubmed.ncbi.nlm.nih.gov/32610682/. DOI: 10.3390/ijms21134627.
12. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis[J]. Nat Immunol, 2010, 11(9): 785-797. DOI: 10.1038/ni.1923.
13. Menny A, Serna M, Boyd C M, et al. CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers[J/OL]. Nat Commun, 2018, 9(1): 5316[2018-12-14]. https://pubmed.ncbi.nlm.nih.gov/30552328/. DOI: 10.1038/s41467-018-07653-5.
14. Noris M, Remuzzi G. Overview of complement activation and regulation[J]. Semin Nephrol, 2013, 33(6): 479-492. DOI: 10.1016/j.semnephrol.2013.08.001.
15. Black JR, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation[J]. Genet Med, 2016, 18(4): 283-289. DOI: 10.1038/gim.2015.70.
16. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration[J]. Nat Genet, 2013, 45(4): 433-439. DOI: 10.1038/ng.2578.
17. Yanagisawa S, Kondo N, Miki A, et al. A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population[J/OL]. PLoS One, 2011, 6(12): e28847[2011-12-12]. https://pubmed.ncbi.nlm.nih.gov/22174912/. DOI: 10.1371/journal.pone.0028847.
18. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration[J]. N Engl J Med, 2007, 357(6): 553-561. DOI: 10.1056/NEJMoa072618.
19. Sofat R, Casas JP, Webster AR, et al. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype[J]. Int J Epidemiol, 2012, 41(1): 250-262. DOI: 10.1093/ije/dyr204.
20. Wang Q, Zhao HS, Li L. Association between complement factor I gene polymorphisms and the risk of age-related macular degeneration: a meta-analysis of literature[J]. Int J Ophthalmol, 2016, 9(2): 298-305. DOI: 10.18240/ijo.2016.02.23.
21. Nishiguchi KM, Yasuma TR, Tomida D, et al. C9-R95X polymorphism in patients with neovascular age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2012, 53(1): 508-512. DOI: 10.1167/iovs.11-8425.
22. Jensen EG, Jakobsen TS, Thiel S, et al. Associations between the complement system and choroidal neovascularization in wet age-related macular degeneration[J/OL]. Int J Mol Sci, 2020, 21(24): 9752[2020-12-21]. https://pubmed.ncbi.nlm.nih.gov/33371261/. DOI: 10.3390/ijms21249752.
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