Targeting the complement system in geographic atrophy: mechanisms and therapeutics

References

• Greener M. Prioritising research into age‐related macular degeneration. Prescriber. 2019;30(5):10–17. doi: 10.1002/psb.1759
   Google Scholar
• Schmitz-Valckenberg S, Sahel JA, Danis R, et al. Natural history of geographic atrophy progression secondary to age-related macular degeneration (geographic atrophy progression study). Ophthalmol. 2016 Feb;123(2):361–368. doi: 10.1016/j.ophtha.2015.09.036
   PubMed Web of Science ®Google Scholar
• Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013 Apr 15;190(8):3831–3838
   PubMed Web of Science ®Google Scholar
• Wu Y, Wei Q, Yu J. The cGAS/STING pathway: a sensor of senescence-associated DNA damage and trigger of inflammation in early age-related macular degeneration. Clin Interv Aging. 2019;14: 1277–1283. doi: 10.2147/CIA.S200637
   PubMed Web of Science ®Google Scholar
• Ricklin D, Lambris JD. New milestones ahead in complement-targeted therapy. Semin Immunol. 2016 Jun;28(3):208–222. doi: 10.1016/j.smim.2016.06.001
   PubMed Web of Science ®Google Scholar
• Kunchithapautham K, Atkinson C, Rohrer B. Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation. J Biol Chem. 2014 May 23;289(21):14534–14546
   PubMed Web of Science ®Google Scholar
• Armento A, Ueffing M, Clark SJ. The complement system in age-related macular degeneration. Cell Mol Life Sci. 2021 May;78(10):4487–4505. doi: 10.1007/s00018-021-03796-9
   PubMed Web of Science ®Google Scholar
• Altay HY, Ozdemir F, Afghah F, et al. Gene regulatory and gene editing tools and their applications for retinal diseases and neuroprotection: from proof-of-concept to clinical trial. Front Neurosci. 2022;16:924917. doi: 10.3389/fnins.2022.924917
   PubMed Web of Science ®Google Scholar
• Dreismann AK, McClements ME, Barnard AR, et al. Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells. Gene Ther. 2021 May;28(5):265–276. doi: 10.1038/s41434-021-00239-9
   PubMed Web of Science ®Google Scholar
• Maugeri A, Barchitta M, Mazzone MG, et al. Complement system and age-related macular degeneration: implications of gene-environment interaction for preventive and personalized medicine. Biomed Res Int. 2018;2018:7532507. doi: 10.1155/2018/7532507
   PubMed Web of Science ®Google Scholar
• Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol. 2007 Nov;25(11):1265–1275. doi: 10.1038/nbt1342.
   PubMed Web of Science ®Google Scholar
• Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the complete study. Ophthalmol. 2014 Mar;121(3):693–701. doi: 10.1016/j.ophtha.2013.09.044
   PubMed Web of Science ®Google Scholar
• Trouw LA, Pickering MC, Blom AM. The complement system as a potential therapeutic target in rheumatic disease. Nat Rev Rheumatol. 2017 Sep;13(9):538–547. doi: 10.1038/nrrheum.2017.125
   PubMed Web of Science ®Google Scholar
• Xu H, Chen M. Targeting the complement system for the management of retinal inflammatory and degenerative diseases. Eur J Pharmacol. 2016 Sep 15;787:94–104. doi: 10.1016/j.ejphar.2016.03.001
   PubMed Web of Science ®Google Scholar
• Charbel Issa P, Chong NV, Scholl HP. The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application. Graefes Arch Clin Exp Ophthalmol. 2011 Feb;249(2):163–174. doi: 10.1007/s00417-010-1568-6
   PubMed Web of Science ®Google Scholar
• Brennan FH, Lee JD, Ruitenberg MJ, et al. Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions. Semin Immunol. 2016 Jun;28(3):292–308. doi: 10.1016/j.smim.2016.03.015
   PubMed Web of Science ®Google Scholar
• Garred P, Tenner AJ, Mollnes TE, et al. Therapeutic targeting of the complement system: from rare diseases to pandemics. Pharmacol Rev. 2021 Apr;73(2):792–827. doi: 10.1124/pharmrev.120.000072
   PubMed Web of Science ®Google Scholar
• Weber BH, Charbel Issa P, Pauly D, et al. The role of the complement system in age-related macular degeneration. Dtsch Arztebl Int. 2014 Feb 21;111(8):133–138. doi: 10.3238/arztebl.2014.0133
   PubMed Web of Science ®Google Scholar
• Troutbeck R, Al-Qureshi S, Guymer RH. Therapeutic targeting of the complement system in age-related macular degeneration: a review. Clin Exp Ophthalmol. 2012 Jan;40(1):18–26. doi: 10.1111/j.1442-9071.2011.02581.x
   PubMed Web of Science ®Google Scholar
• Nebbioso M, Lambiase A, Cerini A, et al. Therapeutic approaches with intravitreal injections in geographic atrophy secondary to age-related macular degeneration. IJMS. 2019 Apr 4;20(7):1693. doi: 10.3390/ijms20071693
   Google Scholar
• Lynch AM, Mandava N, Patnaik JL, et al. Systemic activation of the complement system in patients with advanced age-related macular degeneration. Eur J Ophthalmol. 2020 Sep;30(5):1061–1068. doi: 10.1177/1120672119857896
   PubMed Web of Science ®Google Scholar
• Halawa OA, Lin JB, Miller JW, et al. A Review of completed and ongoing complement inhibitor trials for geographic atrophy secondary to age-related macular degeneration. J Clin Med. 2021 Jun 11;10(12):2580. doi: 10.3390/jcm10122580
   PubMed Web of Science ®Google Scholar
• Kvanta A, Grudzinska MK. Stem cell-based treatment in geographic atrophy: promises and pitfalls. Acta Ophthalmol. 2014 Feb;92(1):21–26. doi: 10.1111/aos.12185
   PubMed Web of Science ®Google Scholar
• Ricklin D, Mastellos DC, Lambris JD. Therapeutic targeting of the complement system. Nat Rev Drug Discov. 2019 Dec 9; doi: 10.1038/s41573-019-0055-y
   Google Scholar
• Asavapanumas N, Tradtrantip L, Verkman AS. Targeting the complement system in neuromyelitis optica spectrum disorder. Expert Opin Biol Ther. 2021 Aug;21(8):1073–1086. doi: 10.1080/14712598.2021.1884223
   PubMed Web of Science ®Google Scholar
• Demirs JT, Yang J, Crowley MA, et al. Differential and altered spatial distribution of complement expression in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2021 Jun 1;62(7):26. doi: 10.1167/iovs.62.7.26
   PubMed Web of Science ®Google Scholar
• Kim BJ, Mastellos DC, Li Y, et al. Targeting complement components C3 and C5 for the retina: key concepts and lingering questions. Prog Retin Eye Res. 2021 Jul;83:100936.
   PubMed Web of Science ®Google Scholar
• Marsh JE, Pratt JR, Sacks SH. Targeting the complement system. Curr Opin Nephrol Hypertens. 1999 Sep;8(5):557–562. doi: 10.1097/00041552-199909000-00004
   PubMed Web of Science ®Google Scholar
• Kandasamy R, Wickremasinghe S, Guymer R. New treatment modalities for geographic atrophy. Asia Pac J Ophthalmol (Phila). 2017 Nov;6(6):508–513. doi: 10.22608/APO.2017262
   PubMedGoogle Scholar
• Lin JB, Halawa OA, Miller JW, et al. Complement inhibition for geographic atrophy: a tempting target with mixed results. J Clin Med. 2021 Jun 29;10(13):2890. doi: 10.3390/jcm10132890
   PubMed Web of Science ®Google Scholar
• Patel PN, Patel PA, Land MR, et al. Targeting the complement cascade for treatment of dry age-related macular degeneration. Biomedicines. 2022 Aug 4;10(8):1884. doi: 10.3390/biomedicines10081884
   PubMed Web of Science ®Google Scholar
• Desai D, Dugel PU. Complement cascade inhibition in geographic atrophy: a review. Eye (Lond). 2022 Feb;36(2):294–302. doi: 10.1038/s41433-021-01765-x
   PubMed Web of Science ®Google Scholar
• Spaide RF, Vavvas DG. Complement inhibition for geographic atrophy: review of salient functional outcomes and perspective. Retina. 2023 Jul 1;43(7):1064–1069.
   PubMed Web of Science ®Google Scholar
• Wykoff CC, Hershberger V, Eichenbaum D, et al. Inhibition of complement factor 3 in geographic atrophy with NGM621: phase 1 dose-escalation study results. Am J Ophthalmol. 2022 Mar;235:131–142
   PubMed Web of Science ®Google Scholar
• 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 May;29(5–a Suppl):S2–S11. doi: 10.18553/jmcp.2023.29.5-a.s2
   PubMed Web of Science ®Google Scholar
• Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmol. 2018 Mar;125(3):369–390. doi: 10.1016/j.ophtha.2017.08.038
   PubMed Web of Science ®Google Scholar
• Zhang JY, Xie B, Barba H, et al. Absence of gut microbiota is associated with RPE/Choroid transcriptomic changes related to age-related macular degeneration pathobiology and decreased choroidal neovascularization. Int J Mol Sci. 2022 Aug 26;23(17):9676. doi: 10.3390/ijms23179676
   PubMed Web of Science ®Google Scholar
• Somasundaran S, Constable IJ, Mellough CB, et al. Retinal pigment epithelium and age-related macular degeneration: a review of major disease mechanisms. Clin Exp Ophthalmol. 2020 Nov;48(8):1043–1056. doi: 10.1111/ceo.13834
   PubMed Web of Science ®Google Scholar
• Zhang G, Fu DJ, Liefers B, et al. Clinically relevant deep learning for detection and quantification of geographic atrophy from optical coherence tomography: a model development and external validation study. Lancet Digit Health. 2021 Oct;3(10):e665–e675. doi: 10.1016/S2589-7500(21)00134-5
   PubMedGoogle Scholar
• Holers VM, Tomlinson S, Kulik L, et al. New therapeutic and diagnostic opportunities for injured tissue-specific targeting of complement inhibitors and imaging modalities. Semin Immunol. 2016 Jun;28(3):260–267. doi: 10.1016/j.smim.2016.05.007
   PubMed Web of Science ®Google Scholar
• Kim DY, Fingler J, Zawadzki RJ, et al. Optical imaging of the chorioretinal vasculature in the living human eye. Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14354–14359. doi: 10.1073/pnas.1307315110
   PubMed Web of Science ®Google Scholar
• Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, et al. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017 May;37(5):819–835. doi: 10.1097/IAE.0000000000001392
   PubMed Web of Science ®Google Scholar
• Wang JH, Wong RCB, Liu GS. Retinal aging transcriptome and cellular landscape in association with the progression of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2023 Apr 3;64(4):32
   PubMed Web of Science ®Google Scholar
• Clark SJ, Bishop PN. The eye as a complement dysregulation hotspot. Semin Immunopathol. 2018 Jan;40(1):65–74. doi: 10.1007/s00281-017-0649-6
   PubMed Web of Science ®Google Scholar
• Barratt J, Weitz I. Complement factor D as a strategic target for regulating the alternative complement pathway. Front Immunol. 2021;12:712572. doi: 10.3389/fimmu.2021.712572
   PubMed Web of Science ®Google Scholar
• Fernandez-Godino R, Pierce EA. C3a triggers formation of sub-retinal pigment epithelium deposits via the ubiquitin proteasome pathway. Sci Rep. 2018 Jun 26;8(1):9679.
   PubMedGoogle Scholar
• Ricklin D. Manipulating the mediator: modulation of the alternative complement pathway C3 convertase in health, disease and therapy. Immunobiology. 2012 Nov;217(11):1057–1066. doi: 10.1016/j.imbio.2012.07.016
   PubMed Web of Science ®Google Scholar
• Hollyfield JG, Bonilha VL, Rayborn ME, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med. 2008 Feb;14(2):194–198. doi: 10.1038/nm1709
   PubMed Web of Science ®Google Scholar
• Pilgrim MG, Lengyel I, Lanzirotti A, et al. Subretinal pigment epithelial deposition of drusen components including hydroxyapatite in a primary cell culture model. Invest Ophthalmol Vis Sci. 2017 Feb 1;58(2):708–719. doi: 10.1167/iovs.16-21060
   PubMed Web of Science ®Google Scholar
• Hakroush S, Kluge IA, Baier E, et al. Relevance of complement C4 deposits localized to distinct Vascular compartments in ANCA-Associated renal vasculitis. Int J Mol Sci. 2022 Nov 18;23(22):14325. doi: 10.3390/ijms232214325
   PubMed Web of Science ®Google Scholar
• Guerra MH, Yumnamcha T, Singh LP, et al. Relative contribution of different mitochondrial oxidative phosphorylation components to the retinal pigment epithelium barrier function: implications for RPE-Related retinal diseases. Int J Mol Sci. 2021 Jul 29;22(15):8130. doi: 10.3390/ijms22158130
   PubMed Web of Science ®Google Scholar
• Zhang J, Li S, Hu S, et al. Association between genetic variation of complement C3 and the susceptibility to advanced age-related macular degeneration: a meta-analysis. BMC Ophthalmol. 2018 Oct 23;18(1):274. doi: 10.1186/s12886-018-0945-5
   PubMedGoogle Scholar
• Mastellos DC, Ricklin D, Lambris JD. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov. 2019 Sep;18(9):707–729. doi: 10.1038/s41573-019-0031-6
   PubMed Web of Science ®Google Scholar
• Holz FG, Sadda SR, Busbee B, et al. 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 Jun 1;136(6):666–677. doi: 10.1001/jamaophthalmol.2018.1544
   PubMed Web of Science ®Google Scholar
• Khanani AM, Thomas MJ, Aziz AA, et al. Review of gene therapies for age-related macular degeneration. Eye (Lond). 2022 Feb;36(2):303–311. doi: 10.1038/s41433-021-01842-1
   PubMed Web of Science ®Google Scholar
• Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor Avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a Randomized pivotal phase 2/3 trial. Ophthalmol. 2021 Apr;128(4):576–586. doi: 10.1016/j.ophtha.2020.08.027
   PubMed Web of Science ®Google Scholar
• Schaal KB, Rosenfeld PJ, Gregori G, et al. Anatomic clinical trial endpoints for nonexudative age-related macular degeneration. Ophthalmol. 2016 May;123(5):1060–1079. doi: 10.1016/j.ophtha.2016.01.034
   PubMed Web of Science ®Google Scholar
• Chakravarthy U, Armendariz BG, Fauser S. 15 years of anti-VEGF treatment for nAMD: success or failure or something in between? Eye (Lond). 2022 Dec;36(12):2232–2233. doi: 10.1038/s41433-022-02153-9
   PubMed Web of Science ®Google Scholar
• Yaspan BL, Williams DF, Holz FG, et al. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci Transl Med. 2017 Jun 21;9(395): doi: 10.1126/scitranslmed.aaf1443
   PubMed Web of Science ®Google Scholar
• Annexon presents archer trial results at asrs 2023 highlighting potential of anx007 as a differentiated treatment for geographic atrophy [Internet]. 2023. https://ir.onbio.com/news-releases/news-release-details/on-presents-archer-trial-results-asrs-2023-highlighting
   Google Scholar
• Apellis announces 24-month results showing increased effects over time with pegcetacoplan in phase 3 DERBY and OAKS studies in geographic atrophy (GA) [Internet]. Online; 2022. https://investors.apellis.com/news-releases/news-release-details/apellis-announces-24-month-results-showing-increased-effects
   Google Scholar
• Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. The Lancet. doi: 10.1016/S0140-6736(23)01520-9
   Google Scholar
• Apellis. Apellis provides updates on injection kits and rare safety events with SYFOVRE® (pegcetacoplan injection). 2023 Aug. https://investors.apellis.com/news-releases/news-release-details/apellis-provides-updates-injection-kits-and-rare-safety-events
   Google Scholar
• Patel SS, Lally DR, Hsu J, et al. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye. 2023 Mar 24. doi: 10.1038/s41433-023-02497-w
   Web of Science ®Google Scholar
• Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. The Lancet. [Internet]. 2022. doi: 10.1016/S0140-6736(23)01583-0
   Google Scholar
• Overview of GATHER1 and GATHER2 Studies: Part 1. Apr 2023.
   Google Scholar
• Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. 2015 Dec;14(12):857–877. doi: 10.1038/nrd4657
   PubMed Web of Science ®Google Scholar
• Armstrong M. NGM clings to hopes despite Catalina crash. 2022. https://www.evaluate.com/vantage/articles/news/trial-results-snippets/ngm-clings-hopes-despite-catalina-crash
   Google Scholar
• Clark SJ, McHarg S, Tilakaratna V, et al. Bruch’s membrane compartmentalizes complement regulation in the Eye with implications for therapeutic design in age-related macular degeneration. Front Immunol. 2017;8:1778. doi: 10.3389/fimmu.2017.01778
   PubMed Web of Science ®Google Scholar
• Braun PX, Mehta N, Gendelman I, et al. Global analysis of macular choriocapillaris perfusion in dry age-related macular degeneration using swept-source Optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2019 Dec 2;60(15):4985–4990. doi: 10.1167/iovs.19-27861
   PubMed Web of Science ®Google Scholar
• Park YG, Park YS, Kim IB. Complement system and potential therapeutics in age-related macular degeneration. Int J Mol Sci. 2021 Jun 25;22(13):6851
   PubMed Web of Science ®Google Scholar
• Gehrs KM, Jackson JR, Brown EN, et al. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010 Mar;128(3):349–358. doi: 10.1001/archophthalmol.2010.18
   PubMedGoogle Scholar
• Dreismann AK, Hallam TM, Tam LC, et al. Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway. Immunol Rev. 2023 Jan;313(1):402–419. doi: 10.1111/imr.13149
   PubMed Web of Science ®Google Scholar
• Becker K, Weigelt CM, Fuchs H, et al. Transcriptome analysis of AAV-induced retinopathy models expressing human VEGF, TNF-alpha, and IL-6 in murine eyes. Sci Rep. 2022 Nov 12;12(1):19395. doi: 10.1038/s41598-022-23065-4
   PubMed Web of Science ®Google Scholar
• Feng R, Patil S, Zhao X, et al. RNA therapeutics - research and clinical advancements. Front Mol Biosci. 2021;8:710738. doi: 10.3389/fmolb.2021.710738
   PubMed Web of Science ®Google Scholar
• Huda R, Tuzun E, Christadoss P. Targeting complement system to treat myasthenia gravis. Rev Neurosci. 2014;25(4):575–583. doi: 10.1515/revneuro-2014-0021
   PubMed Web of Science ®Google Scholar