1. Rein DB, Wittenborn JS, Zhang X, et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol 2009;127:533-40.
2. Wong WL, Su X, Li X, et al. 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:e106-16.
3. DeAngelis MM, Owen LA, Morrison MA, et al. Genetics of age-related macular degeneration (AMD). Hum Mol Genet 2017;26:R45-50.
4. Sobrin L, Seddon JM. Nature and nurture- genes and environment- predict onset and progression of macular degeneration. Prog Retin Eye Res 2014;40:1-15.
5. Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet 2016;48:134-43.
6. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol 1997;123:199-206.
7. Seddon JM, Cote J, Page WF, et al. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 2005;123:321-7.
8. Shahid H, Khan JC, Cipriani V, et al. Age-related macular degeneration: the importance of family history as a risk factor. Br J Ophthalmol 2012;96:427-31.
9. Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010;29:95-112.
10. Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 2012;7:748-56.
11. McAvoy CE, Silvestri G. Retinal changes associated with type 2 glomerulonephritis. Eye (Lond) 2005;19:985-9.
12. Warwick A, Gibson J, Sood R, et al. A rare penetrant TIMP3 mutation confers relatively late onset choroidal neovascularisation which can mimic age-related macular degeneration. Eye (Lond) 2016;30:488-91.
13. Warwick A, Lotery A. Genetics and genetic testing for age-related macular degeneration. Eye (Lond) 2018;32:849-57.
14. Hageman GS, Anderson DH, Johnson LV, 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;102:7227-32.
15. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419-21.
16. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-9.
17. Dinu V, Miller PL, Zhao H. Evidence for association between multiple complement pathway genes and AMD. Genet Epidemiol 2007;31:224-37.
18. Ennis S, Jomary C, Mullins R, et al. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet 2008;372:1828-34.
19. Fagerness JA, Maller JB, Neale BM, et al. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009;17:100-4.
20. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006;38:458-62.
21. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007;357:553-61.
22. Eichler EE, Flint J, Gibson G, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 2010;11:446-50.
23. Raychaudhuri S, Iartchouk O, Chin K, et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet 2011;43:1232-6.
24. Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 2013;45:1366-70.
25. van de Ven JP, Nilsson SC, Tan PL, et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet 2013;45:813-7.
26. Geerlings MJ, Kremlitzka M, Bakker B, et al. The Functional Effect of Rare Variants in Complement Genes on C3b Degradation in Patients With Age-Related Macular Degeneration. JAMA Ophthalmol 2017;135:39-46.
27. Triebwasser MP, Roberson ED, Yu Y, et al. Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2015;56:6873-8.
28. Jakobsdottir J, Conley YP, Weeks DE, et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005;77:389-407.
29. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992-3.
30. Grassmann F, Heid IM, Weber BH, et al. Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration. Genetics 2017;205:919-24.
31. Stanton CM, Chalmers KJ, Wright AF. The chromosome 10q26 susceptibility locus in age-related macular degeneration. Adv Exp Med Biol 2012;723:365-70.
32. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration. Nat Genet 2013;45:433-9, 439e1-2.
33. Seddon JM, Francis PJ, George S, et al. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 2007;297:1793-800.
34. Seddon JM. Macular Degeneration Epidemiology: Nature-Nurture, Lifestyle Factors, Genetic Risk, and Gene-Environment Interactions - The Weisenfeld Award Lecture. Invest Ophthalmol Vis Sci 2017;58:6513-28.
35. Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. Hum Genomics 2011;5:420-40.
36. Perlee LT, Bansal AT, Gehrs K, et al. Inclusion of genotype with fundus phenotype improves accuracy of predicting choroidal neovascularization and geographic atrophy. Ophthalmology 2013;120:1880-92.
37. Chiu CJ, Mitchell P, Klein R, et al. A risk score for the prediction of advanced age-related macular degeneration: development and validation in 2 prospective cohorts. Ophthalmology 2014;121:1421-7.
38. Assel MJ, Li F, Wang Y, et al. Genetic Polymorphisms of CFH and ARMS2 Do Not Predict Response to Antioxidants and Zinc in Patients with Age-Related Macular Degeneration: Independent Statistical Evaluations of Data from the Age-Related Eye Disease Study. Ophthalmology 2018;125:391-7.
39. Vavvas DG, Small KW, Awh CC, et al. CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation. Proc Natl Acad Sci U S A 2018;115:E696-704.
40. Sardell RJ, Persad PJ, Pan SS, et al. Progression Rate From Intermediate to Advanced Age-Related Macular Degeneration Is Correlated With the Number of Risk Alleles at the CFH Locus. Invest Ophthalmol Vis Sci 2016;57:6107-15.
41. Hagstrom SA, Ying GS, Pauer GJT, et al. Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT). Ophthalmology 2013;120:593-9.
42. Lotery AJ, Gibson J, Cree AJ, et al. Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN Study. Ophthalmology 2013;120:2637-43.
43. Lorés-Motta L, de Jong EK, den Hollander AI. Exploring the Use of Molecular Biomarkers for Precision Medicine in Age-Related Macular Degeneration. Mol Diagn Ther 2018;22:315-43.
44. Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology 2018;125:842-9.
45. Holekamp N, Wykoff CC, Schmitz-Valckenberg S, et al. Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials. Ophthalmology 2020;127:769-83.
46. Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials. Ophthalmology 2007;114:271-7.
47. Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol 2007;143:463-72.
48. 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;136:666-77.
49. 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). Ophthalmology 2016;123:361-8.
50. Age-Related Eye Disease Study 2. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol 2014;132:142-9.
51. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-36.
52. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev 2017;7:CD000254.
53. Heier JS, Brown DM, Shah SP, et al. Intravitreal Aflibercept Injection vs Sham as Prophylaxis Against Conversion to Exudative Age-Related Macular Degeneration in High-risk Eyes: A Randomized Clinical Trial. JAMA Ophthalmol 2021;139:542-7.
54. Allingham MJ, Mettu PS, Cousins SW. Elamipretide, a Mitochondrial-Targeted Drug, for the Treatment of Vision Loss in Dry AMD with High Risk Drusen: Results of the Phase 1 ReCLAIM Study. Invest Ophthalmol Vis Sci 2019;60:361.
55. Shaw LT, Mackin A, Shah R, et al. Risuteganib-a novel integrin inhibitor for the treatment of non-exudative (dry) age-related macular degeneration and diabetic macular edema. Expert Opin Investig Drugs 2020;29:547-54.
56. Puliafito CA, Wykoff CC. New Frontiers in Retina: highlights of the 2020 angiogenesis, exudation and degeneration symposium. Int J Retina Vitreous 2020;6:18.
57. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. Ophthalmology 2020;127:186-95.
58. Kuppermann BD, Patel SS, Boyer DS, et al. Phase 2 study of the safety and efficacy of brimonidine drug delivery system (BRIMO DDS) generation 1 in patients with geographic atrophy secondary to age-related macular degeneration. Retina 2021;41:144-55.
59. Fuma S, Murase H, Kuse Y, et al. Photobiomodulation with 670 nm light increased phagocytosis in human retinal pigment epithelial cells. Mol Vis 2015;21:883-92.
60. Merry GF, Munk MR, Dotson RS, et al. Photobiomodulation reduces drusen volume and improves visual acuity and contrast sensitivity in dry age-related macular degeneration. Acta Ophthalmol 2017;95:e270-7.
61. Munk MR, Markowitz SN, Devenyi R, et al. Final Analysis of LIGHTSITE I: A Double-Masked, Randomized, Sham-Controlled Study with Photobiomodulation in Dry Age-Related Macular Degeneration Subjects. Invest Ophthalmol Vis Sci 2018;59:2415.
62. Markowitz SN, Devenyi RG, Munk MR, et al. A double-masked, randomized, sham-controlled, single-center study with photobiomodulation for the treatment of dry age-related macular degeneration. Retina 2020;40:1471-82.
63. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 2013;120:2292-9.
64. Al-Khersan H, Hussain RM, Ciulla TA, et al. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother 2019;20:1879-91.
65. Khurana RN, Kunimoto D, Yoon YH, et al. Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration. Ophthalmology 2021;128:1027-38.
66. Sahni J, Patel SS, Dugel PU, et al. Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial. Ophthalmology 2019;126:1155-70.
67. Sahni J, Dugel PU, Patel SS, et al. Safety and Efficacy of Different Doses and Regimens of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial. JAMA Ophthalmol 2020;138:955-63.
68. Dugel PU, Boyer DS, Antoszyk AN, et al. Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration. Ophthalmol Retina 2020;4:250-63.
69. Campochiaro PA, Marcus DM, Awh CC, et al. The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. Ophthalmology 2019;126:1141-54.
70. Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J Clin Invest 2019;129:4901-11.
71. Anguela XM, High KA. Entering the Modern Era of Gene Therapy. Annu Rev Med 2019;70:273-88.
72. Weng CY. Bilateral Subretinal Voretigene Neparvovec-rzyl (Luxturna) Gene Therapy. Ophthalmol Retina 2019;3:450.
73. Ramlogan-Steel CA, Murali A, Andrzejewski S, et al. Gene therapy and the adeno-associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations. Clin Exp Ophthalmol 2019;47:521-36.
74. Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond) 2016;3:34.
75. Stone EM. Genetic testing for age-related macular degeneration: not indicated now. JAMA Ophthalmol 2015;133:598-600.
76. Guimaraes TAC, Georgiou M, Bainbridge JWB, et al. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol 2021;105:151-7.
77. Arcondéguy T, Lacazette E, Millevoi S, et al. VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res 2013;41:7997-8010.
78. Dehghanian F, Hojati Z, Kay M. New Insights into VEGF-A Alternative Splicing: Key Regulatory Switching in the Pathological Process. Avicenna J Med Biotechnol 2014;6:192-9.
79. Bordet T, Behar-Cohen F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discov Today 2019;24:1685-93.
80. Cashman SM, Ramo K, Kumar-Singh R. A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. PLoS One 2011;6:e19078.
81. Puliafito CA, Wykoff CC. Looking ahead in retinal disease management: highlights of the 2019 angiogenesis, exudation and degeneration symposium. Int J Retina Vitreous 2019;5:22.
82. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A 1993;90:10705-9.
83. Owen LA, Morrison MA, Ahn J, et al. FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression. Invest Ophthalmol Vis Sci 2014;55:3543-54.
84. Constable IJ, Lai CM, Magno AL, et al. Gene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial. Am J Ophthalmol 2017;177:150-8.
85. Rakoczy EP, Lai CM, Magno AL, et al. Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. Lancet 2015;386:2395-403.
86. Rakoczy EP, Magno AL, Lai CM, et al. Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. Am J Ophthalmol 2019;204:113-23.
87. Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017;390:50-61.
88. Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration. Mol Ther 2019;27:118-29.
89. Liu Y, Fortmann SD, Shen J, et al. AAV8-antiVEGFfab Ocular Gene Transfer for Neovascular Age-Related Macular Degeneration. Mol Ther 2018;26:542-9.
90. Binley K, Widdowson PS, Kelleher M, et al. Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat(?), for age-related macular degeneration. Hum Gene Ther 2012;23:980-91.
91. Campochiaro PA, Lauer AK, Sohn EH, et al. Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study. Hum Gene Ther 2017;28:99-111.
92. Rasmussen H, Chu KW, Campochiaro P, et al. Clinical protocol. An open-label, phase I, single administration, dose-escalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD). Hum Gene Ther 2001;12:2029-32.
93. Campochiaro PA, Nguyen QD, Shah SM, et al. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 2006;17:167-76.
94. Kumar-Singh R. The role of complement membrane attack complex in dry and wet AMD - From hypothesis to clinical trials. Exp Eye Res 2019;184:266-77.
95. Guzman-Aranguez A, Loma P, Pintor J. Small-interfering RNAs (siRNAs) as a promising tool for ocular therapy. Br J Pharmacol 2013;170:730-47.
96. Nguyen QD, Schachar RA, Nduaka CI, et al. Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study). Ophthalmology 2012;119:1867-73.
97. Cohen MN, O'Shaughnessy D, Fisher K, et al. APEX: a phase II randomised clinical trial evaluating the safety and preliminary efficacy of oral X-82 to treat exudative age-related macular degeneration. Br J Ophthalmol 2021;105:716-22.
98. Poor SH, Adams CM, Ferriere M, et al. Topical VEGF receptor inhibitor, LHA510, did not demonstrate efficacy in a Proof-of-Concept study in patients with neovascular age-related macular degeneration (nv AMD). Invest Ophthalmol Vis Sci 2018;59:2394.