Top

Published in:

01-02-2022 | Macular Degeneration | Leading Article

Complement Mediators in Development to Treat Age-Related Macular Degeneration

Authors: Marcella Nebbioso, Federica Franzone, Alessandro Lambiase, Samanta Taurone, Marco Artico, Magda Gharbiya, Antonio Greco, Antonella Polimeni

Published in: Drugs & Aging | Issue 2/2022

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.

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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).CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.PubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

54.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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).CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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).CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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].CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

Title: Complement Mediators in Development to Treat Age-Related Macular Degeneration
Authors: Marcella Nebbioso
Federica Franzone
Alessandro Lambiase
Samanta Taurone
Marco Artico
Magda Gharbiya
Antonio Greco
Antonella Polimeni
Publication date: 01-02-2022
Publisher: Springer International Publishing
Keyword: Macular Degeneration
Published in: Drugs & Aging / Issue 2/2022
Print ISSN: 1170-229X
Electronic ISSN: 1179-1969
DOI: https://doi.org/10.1007/s40266-021-00914-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2022

Pharmacological Treatment in the Management of Glenohumeral Osteoarthritis

Topical Pharmacotherapy for Actinic Keratoses in Older Adults

Medical Cannabis Use Among Older Adults in Canada: Self-Reported Data on Types and Amount Used, and Perceived Effects

Correction to: Assessment of Comorbidity Burden and Treatment Response: Reanalysis of the SCD-HEFT Trial

Which Potentially Inappropriate Medications List Can Detect Patients At Risk of Readmissions in the Older Adult Population Admitted for Falls? An Observational Multicentre Study Using a Clinical Data Warehouse

Neuropsychiatric Systemic Lupus Erythematosus in Older Adults: Diagnosis and Management

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials