Skip to main content

Advertisement

Log in

Complement Mediators in Development to Treat Age-Related Macular Degeneration

  • Leading Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Over recent years, great attention has been paid to the role of the complement system in the pathogenesis of age-related macular degeneration (AMD). In particular, several studies have highlighted a link between AMD development and complement dysregulation, which can probably be explained as a complement cascade hyperactivation resulting from the presence of a series of risk factors such as aging; smoking; obesity; alcohol consumption; exposure to pesticides, industrial chemicals, or pollution; and other causes of oxidative stress. This hypothesis has been mainly supported by the presence of complement mediators as constituents of drusen, representing one of the earliest and most characteristic signs of retinal damage in AMD. Additionally, activated complement mediators and some complement regulators, such as vitronectin, have been found not only in the drusen and adjacent retinal areas but also in the peripheral blood of patients with AMD. Therefore, we aim to provide a review of recently studied complement factors to highlight their role in the pathogenesis of AMD and to evaluate new potential therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358(24):2606–17. https://doi.org/10.1056/NEJMra0801537.Erratum.In:NEnglJMed.2008;359(16):1736.

    Article  CAS  PubMed  Google Scholar 

  2. Klein BE, Klein R, Lee KE. Incidence of age-related cataract over a 10-year interval: the Beaver Dam Eye Study. Ophthalmology. 2002;109(11):2052–7. https://doi.org/10.1016/s0161-6420(02)01249-6.

    Article  PubMed  Google Scholar 

  3. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106–16. https://doi.org/10.1016/S2214-109X(13)70145-1.

    Article  PubMed  Google Scholar 

  4. Halliwell B. Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging. 2001;18(9):685–716. https://doi.org/10.2165/00002512-200118090-00004.

    Article  CAS  PubMed  Google Scholar 

  5. Donders FC. Beiträge zur pathologischen anatomie des auges. Archiv für Ophthalmologie. 1855;1:106–18. https://doi.org/10.1007/BF02720791.

    Article  Google Scholar 

  6. Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ, Ambati J. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103(7):2328–33. https://doi.org/10.1073/pnas.0408835103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH. A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res. 2000;70(4):441–9. https://doi.org/10.1006/exer.1999.0798.

    Article  CAS  PubMed  Google Scholar 

  8. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in drusen formation and age-related macular degeneration. Exp Eye Res. 2001;73(6):887–96. https://doi.org/10.1006/exer.2001.1094.

    Article  CAS  PubMed  Google Scholar 

  9. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102(20):7227–32. https://doi.org/10.1073/pnas.0501536102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kawa MP, Machalinska A, Roginska D, Machalinski B. Complement system in pathogenesis of AMD: dual player in degeneration and protection of retinal tissue. J Immunol Res. 2014;2014: 483960. https://doi.org/10.1155/2014/483960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ferris FL 3rd, Wilkinson CP, Bird A, Chakravarthy U, Chew E, Csaky K, Sadda SR, Beckman Initiative for Macular Research Classification Committee. Clinical classification of age-related macular degeneration. Ophthalmology. 2013;120(4):844–51. https://doi.org/10.1016/j.ophtha.2012.10.036.

    Article  PubMed  Google Scholar 

  12. Michelis G, German OL, Villasmil R, Soto T, Rotstein NP, Politi L, Becerra SP. Pigment epithelium-derived factor (PEDF) and derived peptides promote survival and differentiation of photoreceptors and induce neurite-outgrowth in amacrine neurons. J Neurochem. 2021. https://doi.org/10.1111/jnc.15454.

    Article  PubMed  Google Scholar 

  13. Ying GS, Huang J, Maguire MG, Jaffe GJ, Grunwald JE, Toth C, Daniel E, Klein M, Pieramici D, Wells J, Martin DF, Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration. Ophthalmology. 2013;120(1):122–9. https://doi.org/10.1016/j.ophtha.2012.07.042.

    Article  PubMed  Google Scholar 

  14. Kaiser PK, Brown DM, Zhang K, Hudson HL, Holz FG, Shapiro H, Schneider S, Acharya NR. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol. 2007;144(6):850–7. https://doi.org/10.1016/j.ajo.2007.08.012.

    Article  CAS  PubMed  Google Scholar 

  15. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ, CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908. https://doi.org/10.1056/NEJMoa1102673.

    Article  CAS  PubMed  Google Scholar 

  16. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–31. https://doi.org/10.1056/NEJMoa054481.

    Article  CAS  PubMed  Google Scholar 

  17. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, Reeves BC, IVAN Study Investigators. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399–411. https://doi.org/10.1016/j.ophtha.2012.04.015 (Erratum in: Ophthalmology. 2012;119(8):1508. Erratum in: Ophthalmology. 2013;120(9):1719).

    Article  PubMed  Google Scholar 

  18. Enríquez AB, Baumal CR, Crane AM, Witkin AJ, Lally DR, Liang MC, Enríquez JR, Eichenbaum DA. Early experience with brolucizumab treatment of neovascular age-related macular degeneration. JAMA Ophthalmol. 2021;139(4):441–8. https://doi.org/10.1001/jamaophthalmol.2020.7085.

    Article  PubMed  Google Scholar 

  19. Holz FG, Sadda SR, Busbee B, Chew EY, Mitchell P, Tufail A, Brittain C, Ferara D, Grat S, Honigberg L, Martin J, Tong B, Ehrlich JS, Bressler NM, for the Chroma and Spectri Study Investigators. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol. 2018;136(6):666–77. https://doi.org/10.1001/jamaophthalmol.2018.1544.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lindblad AS, Lloyd PC, Clemons TE, Gensler GR, Ferris FL III, Klein ML, Armstrong JR, Age-Related Eye Disease Study Research Group. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol. 2009;127(9):1168–74. https://doi.org/10.1001/archophthalmol.2009.198.

    Article  PubMed  Google Scholar 

  21. Klein R, Meuer SM, Knudtson MD, Klein BE. The epidemiology of progression of pure geographic atrophy: the Beaver Dam Eye Study. Am J Ophthalmol. 2008;146(5):692–9. https://doi.org/10.1016/j.ajo.2008.05.050.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bindewald A, Schmitz-Valckenberg S, Jorzik JJ, Dolar-Szczasny J, Sieber H, Keilhauer C, Weinberger AW, Dithmar S, Pauleikhoff D, Mansmann U, Wolf S, Holz FG. Classification of abnormal fundus autofluorescence patterns in the junctional zone of geographic atrophy in patients with age related macular degeneration. Br J Ophthalmol. 2005;89(7):874–8. https://doi.org/10.1136/bjo.2004.057794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Keenan TD, Agrón E, Domalpally A, Clemons TE, van Asten F, Wong WT, Danis RG, Sadda S, Rosenfeld PJ, Klein ML, Ratnapriya R, Swaroop A, Ferris FL III, Chew EY, AREDS2 Research Group. Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16. Ophthalmology. 2018;125(12):1913–28. https://doi.org/10.1016/j.ophtha.2018.05.028.

    Article  PubMed  Google Scholar 

  24. Schmitz-Valckenberg S, Sahel JA, Danis R, Fleckenstein M, Jaffe GJ, Wolf S, Pruente C, Holz FG. Natural history of geographic atrophy progression secondary to age-related macular degeneration (Geographic Atrophy Progression Study). Ophthalmology. 2016;123(2):361–8. https://doi.org/10.1016/j.ophtha.2015.09.036.

    Article  PubMed  Google Scholar 

  25. Thorell MR, Goldhardt R, Nunes RP, de Amorim Garcia Filho CA, Abbey AM, Kuriyan AE, Modi YS, Gregori G, Yehoshua Z, Feuer W, Sadda S, Rosenfeld PJ. Association between subfoveal choroidal thickness, reticular pseudodrusen, and geographic atrophy in age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2015;46(5):513–21. https://doi.org/10.3928/23258160-20150521-02.

    Article  PubMed  Google Scholar 

  26. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, Gregori G, Penha FM, Moshfeghi AA, Zhang K, Sadda S, Feuer W, Rosenfeld PJ. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121(3):693–701. https://doi.org/10.1016/j.ophtha.2013.09.044.

    Article  PubMed  Google Scholar 

  27. Moult EM, Alibhai AY, Lee B, Yu Y, Ploner S, Chen S, Maier A, Duker JS, Waheed NK, Fujimoto JG. A framework for multiscale quantitation of relationships between choriocapillaris flow impairment and geographic atrophy growth. Am J Ophthalmol. 2020;214:172–87. https://doi.org/10.1016/j.ajo.2019.12.006.

    Article  PubMed  Google Scholar 

  28. Thulliez M, Zhang Q, Shi Y, Zhou H, Chu Z, de Sisternes L, Durbin MK, Feuer W, Gregori G, Wang RK, Rosenfeld PJ. Correlations between choriocapillaris flow deficits around geographic atrophy and enlargement rates based on swept-source OCT imaging. Ophthalmol Retina. 2019;3(6):478–88. https://doi.org/10.1016/j.oret.2019.01.024.

    Article  PubMed  Google Scholar 

  29. Nebbioso M, Buomprisco G, Pascarella A, Pescosolido N. Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review. Crit Rev Food Sci Nutr. 2017;57(3):559–65. https://doi.org/10.1080/10408398.2014.893504.

    Article  CAS  PubMed  Google Scholar 

  30. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14(7):835–46.

    Article  CAS  Google Scholar 

  31. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Hageman GS, Dean M, Allikmets R, AMD Genetics Clinical Study Group. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38(4):458–62. https://doi.org/10.1038/ng1750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dentchev T, Milam AH, Lee VM, Trojanowski JQ, Dunaief JL. Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol Vis. 2003;9:184–90.

    CAS  PubMed  Google Scholar 

  33. Curcio CA, Presley JB, Malek G, Medeiros NE, Avery DV, Kruth HS. Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res. 2005;81(6):731–41. https://doi.org/10.1016/j.exer.2005.04.012.

    Article  CAS  PubMed  Google Scholar 

  34. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3(11):879–89. https://doi.org/10.1038/nri1224.

    Article  CAS  PubMed  Google Scholar 

  35. Zipfel PF. Complement and immune defense: from innate immunity to human diseases. Immunol Lett. 2009;126(1–2):1–7. https://doi.org/10.1016/j.imlet.2009.07.005.

    Article  CAS  PubMed  Google Scholar 

  36. Schifferli JA, Ng YC, Peters DK. The role of complement and its receptor in the elimination of immune complexes. N Engl J Med. 1986;315(8):488–95. https://doi.org/10.1056/NEJM198608213150805.

    Article  CAS  PubMed  Google Scholar 

  37. Park YG, Park YS, Kim IB. Complement system and potential therapeutics in age-related macular degeneration. Int J Mol Sci. 2021;22(13):6851. https://doi.org/10.3390/ijms22136851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nebbioso M, Lambiase A, Cerini A, Limoli PG, La Cava M, Greco A. Therapeutic approaches with intravitreal injections in geographic atrophy secondary to age-related macular degeneration: current drugs and potential molecules. Int J Mol Sci. 2019;20(7):1693. https://doi.org/10.3390/ijms20071693.

    Article  CAS  PubMed Central  Google Scholar 

  39. de Boer ECW, van Mourik AG, Jongerius I. Therapeutic lessons to be learned from the role of complement regulators as double-edged sword in health and disease. Front Immunol. 2020;11: 578069. https://doi.org/10.3389/fimmu.2020.578069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mullins RF, Schoo DP, Sohn EH, et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. 2014;184(11):3142–53. https://doi.org/10.1016/j.ajpath.2014.07.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48(2):134–43. https://doi.org/10.1038/ng.3448.

    Article  CAS  PubMed  Google Scholar 

  42. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT, Genetic Factors in AMD Study Group. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357(6):553–61. https://doi.org/10.1056/NEJMoa072618.

    Article  CAS  PubMed  Google Scholar 

  43. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007;39(10):1200–1. https://doi.org/10.1038/ng2131.

    Article  CAS  PubMed  Google Scholar 

  44. Li M, Atmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS, Li Y, Liang L, Zareparsi S, Swaroop A, Abecasis GR. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet. 2006;38(9):1049–54. https://doi.org/10.1038/ng1871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77(3):389–407. https://doi.org/10.1086/444437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, Dewan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314(5801):992–3. https://doi.org/10.1126/science.1133811.

    Article  CAS  PubMed  Google Scholar 

  47. Yanagisawa S, Kondo N, Miki A, Matsumiya W, Kusuhara S, Tsukahara Y, Honda S, Negi A. A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population. PLoS ONE. 2011;6(12): e28847. https://doi.org/10.1371/journal.pone.0028847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Spencer KL, Olson LM, Anderson BM, Schnetz-Boutaud N, Scott WK, Gallins P, Agarwal A, Postel EA, Pericak-Vance MA, Haines JL. C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet. 2008;17(12):1821–4. https://doi.org/10.1093/hmg/ddn075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zerbib J, Richard F, Puche N, Leveziel N, Cohen SY, Korobelnik JF, Sahel J, Munnich A, Kaplan J, Rozet JM, Souied EH. R102G polymorphism of the C3 gene associated with exudative age-related macular degeneration in a French population. Mol Vis. 2010;16:1324–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Thakkinstian A, McKay GJ, McEvoy M, Chakravarthy U, Chakrabarti S, Silvestri G, Kaur I, Li X, Attia J. Systematic review and meta-analysis of the association between complement component 3 and age-related macular degeneration: a HuGE review and meta-analysis. Am J Epidemiol. 2011;173(12):1365–79. https://doi.org/10.1093/aje/kwr025.

    Article  PubMed  Google Scholar 

  51. Goto A, Akahori M, Okamoto H, Minami M, Terauchi N, Haruhata Y, Obazawa M, Noda T, Honda M, Mizota A, Tanaka M, Hayashi T, Tanito M, Ogata N, Iwata T. Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J Ocul Biol Dis Infor. 2009;2(4):164–75. https://doi.org/10.1007/s12177-009-9047-1.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Pei XT, Li XX, Bao YZ, Yu WZ, Yan Z, Qi HJ, Qian T, Xiao HX. Association of c3 gene polymorphisms with neovascular age-related macular degeneration in a Chinese population. Curr Eye Res. 2009;34(8):615–22. https://doi.org/10.1080/02713680903003484.

    Article  CAS  PubMed  Google Scholar 

  53. Liu X, Zhao P, Tang S, Lu F, Hu J, Lei C, Yang X, Lin Y, Ma S, Yang J, Zhang D, Shi Y, Li T, Chen Y, Fan Y, Yang Z. Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population. Retina. 2010;30(8):1177–84. https://doi.org/10.1097/IAE.0b013e3181cea676.

    Article  PubMed  Google Scholar 

  54. Hoy SM. Pegcetacoplan: first approval. Drugs. 2021;81(12):1423–30. https://doi.org/10.1007/s40265-021-01560-8.

    Article  CAS  PubMed  Google Scholar 

  55. Steinle NC, Pearce I, Monés J, Metlapally R, Saroj N, Hamdani M, Ribeiro R, Rosenfeld PJ, Lad EM. Impact of baseline characteristics on geographic atrophy progression in the FILLY trial evaluating the complement c3 inhibitor pegcetacoplan. Am J Ophthalmol. 2021;227:116–24. https://doi.org/10.1016/j.ajo.2021.02.031.

    Article  CAS  PubMed  Google Scholar 

  56. Wykoff CC, Rosenfeld PJ, Waheed NK, Singh RP, Ronca N, Slakter JS, Staurenghi G, Monés J, Baumal CR, Saroj N, Metlapally R, Ribeiro R. Characterizing new-onset exudation in the randomized phase 2 FILLY trial of complement inhibitor pegcetacoplan for geographic atrophy. Ophthalmology. 2021;128(9):1325–36. https://doi.org/10.1016/j.ophtha.2021.02.025.

    Article  PubMed  Google Scholar 

  57. Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm. 2015;95(Pt B):158–72. https://doi.org/10.1016/j.ejpb.2015.02.020.

    Article  CAS  PubMed  Google Scholar 

  58. Kassa E, Ciulla TA, Hussain RM, Dugel PU. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin Biol Ther. 2019;19(4):335–42. https://doi.org/10.1080/14712598.2019.1575358.

    Article  CAS  PubMed  Google Scholar 

  59. Jaffe GJ, Westby K, Csaky KG, Monés J, Pearlman JA, Patel SS, Joondeph BC, Randolph J, Masonson H, Rezaei KA. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 Trial. Ophthalmology. 2021;128(4):576–86. https://doi.org/10.1016/j.ophtha.2020.08.027.

    Article  PubMed  Google Scholar 

  60. Pillemer L, Blum L, Lepow IH, Ross OA, Todd EW, Wardlaw AC. The properdin system and immunity. I. Demonstration and isolation of a new serum protein, properdin, and its role in immune phenomena. Science. 1954;120(3112):279–85. https://doi.org/10.1126/science.120.3112.279.

    Article  CAS  PubMed  Google Scholar 

  61. Halili MA, Ruiz-Gómez G, Le GT, Abbenante G, Fairlie DP. Complement component C2, inhibiting a latent serine protease in the classical pathway of complement activation. Biochemistry. 2009;48(35):8466–72. https://doi.org/10.1021/bi900679r (PMID: 19642650).

    Article  CAS  PubMed  Google Scholar 

  62. Varma R, Souied EH, Tufail A, et al. Maximum reading speed in patients with geographic atrophy secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci. 2018;59(4):AMD195–201. https://doi.org/10.1167/iovs.18-24238.

    Article  PubMed  Google Scholar 

  63. Ansari M, McKeigue PM, Skerka C, Hayward C, Rudan I, Vitart V, et al. Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration. Hum Mol Genet. 2013;22(23):4857–69. https://doi.org/10.1093/hmg/ddt336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schmidt CQ, Herbert AP, Mertens HD, Guariento M, Soares DC, Uhrin D, Rowe AJ, Svergun DI, Barlow PN. The central portion of factor H (modules 10–15) is compact and contains a structurally deviant CCP module. J Mol Biol. 2010;395(1):105–22. https://doi.org/10.1016/j.jmb.2009.10.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sánchez-Corral P, Pouw RB, López-Trascasa M, Józsi M. Self-Damage Caused by Dysregulation of the Complement alternative pathway: relevance of the factor H protein family. Front Immunol. 2018;9:1607. https://doi.org/10.3389/fimmu.2018.01607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cipriani V, Tierney A, Griffiths JR, Zuber V, Sergouniotis PI, Yates JRW, Moore AT, Bishop PN, Clark SJ, Unwin RD. Beyond factor H: the impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations. Am J Hum Genet. 2021;108(8):1385–400. https://doi.org/10.1016/j.ajhg.2021.05.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Toomey CB, Johnson LV, Bowes RC. Complement factor H in AMD: bridging genetic associations and pathobiology. Prog Retin Eye Res. 2018;62:38–57. https://doi.org/10.1016/j.preteyeres.2017.09.001.

    Article  CAS  PubMed  Google Scholar 

  68. Scholl HP, Weber BH, Nöthen MM, Wienker T, Holz FG. Y402H-polymorphism in complement factor H and age-related macula degeneration (AMD). Ophthalmologe. 2005;102(11):1029–35. https://doi.org/10.1007/s00347-005-1270-y (German).

    Article  CAS  PubMed  Google Scholar 

  69. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–21. https://doi.org/10.1126/science.1110359.

    Article  CAS  PubMed  Google Scholar 

  70. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–4. https://doi.org/10.1126/science.1110189.

    Article  CAS  PubMed  Google Scholar 

  71. Tian J, Yu W, Qin X, Fang K, Chen Q, Hou J, Li J, Chen D, Hu Y, Li X. Association of genetic polymorphisms and age-related macular degeneration in Chinese population. Invest Ophthalmol Vis Sci. 2012;53(7):4262–9. https://doi.org/10.1167/iovs.11-8542.

    Article  CAS  PubMed  Google Scholar 

  72. Lorés-Motta L, Paun CC, Corominas J, Pauper M, Geerlings MJ, Altay L, Schick T, Daha MR, Fauser S, Hoyng CB, den Hollander AI, de Jong EK. Genome-Wide Association Study reveals variants in CFH and CFHR4 associated with systemic complement activation: implications in age-related macular degeneration. Ophthalmology. 2018;125(7):1064–74. https://doi.org/10.1016/j.ophtha.2017.12.023.

    Article  PubMed  Google Scholar 

  73. Raychaudhuri S, Iartchouk O, Chin K, Tan PL, Tai AK, Ripke S, Gowrisankar S, Vemuri S, Montgomery K, Yu Y, Reynolds R, Zack DJ, Campochiaro B, Campochiaro P, Katsanis N, Daly MJ, Seddon JM. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet. 2011;43(12):1232–6. https://doi.org/10.1038/ng.976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lin MK, Yang J, Hsu CW, Gore A, Bassuk AG, Brown LM, Colligan R, Sengillo JD, Mahajan VB, Tsang SH. HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1. Aging Cell. 2018;17(4): e12710. https://doi.org/10.1111/acel.12710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Williams BL, Seager NA, Gardiner JD, et al. Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium. Proc Natl Acad Sci U S A. 2021;118(30): e2103617118. https://doi.org/10.1073/pnas.2103617118].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Grassmann F, Heid IM, Weber BH, International AMD Genomics Consortium (IAMDGC). Recombinant haplotypes narrow the ARMS2/HTRA1 association signal for age-related macular degeneration. Genetics. 2017;205(2):919–24. https://doi.org/10.1534/genetics.116.195966.

    Article  CAS  PubMed  Google Scholar 

  77. Biasella F, Plössl K, Karl C, Weber BHF, Friedrich U. Altered protein function caused by AMD-associated variant rs704 links vitronectin to disease pathology. Invest Ophthalmol Vis Sci. 2020;61(14):2. https://doi.org/10.1167/iovs.61.14.2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Halawa OA, Lin JB, Miller JW, Vavvas DG. A review of completed and ongoing complement inhibitor trials for geographic atrophy secondary to age-related macular degeneration. J Clin Med. 2021;10:2580. https://doi.org/10.3390/jcm10122580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Jaffe, G.J.; Sahni, J.; Fauser, S.; Geary, R.S.; Schneider, E.; McCaleb, M. Development of IONIS-FB-L Rx to treat geographic atrophy associated with AMD. Invest Ophthalmol Vis Sci. 2020, 61(7), 4305. ARVO Annual Meeting Abstract June 2020.

  80. ClinicalTrials.gov Identifier: NCT04246866 First in Human Study to Evaluate the Safety and Tolerability of GEM103 in Geographic Atrophy Secondary to Dry Age Related Macular Degeneration.

  81. ClinicalTrials.gov Identifier: NCT04643886 A Multiple Dose Study of Repeat Intravitreal Injections of GEM103 in Dry Age-related Macular Degeneration.

  82. Kim JB, Lad EM. Therapeutic options under development for nonneovascular age-related macular degeneration and geographic atrophy. Drugs Aging. 2021;38(1):17–27. https://doi.org/10.1007/s40266-020-00822-6.

    Article  PubMed  Google Scholar 

  83. Jha P, Bora PS, Bora NS. The role of complement system in ocular diseases including uveitis and macular degeneration. Mol Immunol. 2007;44(16):3901–8. https://doi.org/10.1016/j.molimm.2007.06.145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Marcella Nebbioso or Federica Franzone.

Ethics declarations

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflicts of interest

MN, FF, AL, MA, ST, MG, AG, and AP have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

MN and FF performed the research and wrote the paper; MA, ST, and MG contributed to the revision of the manuscript; AL, AG, and AP contributed to the concept and design for important intellectual content.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nebbioso, M., Franzone, F., Lambiase, A. et al. Complement Mediators in Development to Treat Age-Related Macular Degeneration. Drugs Aging 39, 107–118 (2022). https://doi.org/10.1007/s40266-021-00914-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-021-00914-x

Navigation