A number of different approaches are under development for treating nonexudative manifestations of age-related macular degeneration (AMD). Some interventions target specific pathways that are believed to play a role in AMD pathogenesis, e.g. oxidative damage, lipofuscin accumulation, chronic inflammation (including complement activation), extracellular matrix changes (e.g. β-amyloid accumulation), impaired choroidal blood flow, and apoptosis. In principle, these therapies can be combined (‘combination therapy'), which may lead to synergistic effects that include better visual outcome, less likelihood for ‘escape' (i.e. drug resistance), and less frequent treatment.

1.
Zarbin MA, Rosenfeld PJ: Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 2010;30:1350-1367.
2.
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;119:1417-1436.
3.
Omenn GS, Goodman GE, Thornquist MD, et al: Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Nat Cancer Inst 1996;88:1550-1559.
4.
The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-1035.
5.
Moriarty-Craige SE, Adkison J, Lynn M, et al: Antioxidant supplements prevent oxidation of cysteine/cystine redox in patients with age-related macular degeneration. Am J Ophthalmol 2005;140:1020-1026.
6.
Brantley MA Jr, Osborn MP, Sanders BJ, et al: The short-term effects of antioxidant and zinc supplements on oxidative stress biomarker levels in plasma: a pilot investigation. Am J Ophthalmol 2012;153:1104-1109.e2.
7.
Age-Related Eye Disease Study 2 Research Group: Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013;309:2005-2015.
8.
Age-Related Eye Disease Study 2 Research Group; Chew EY, Clemons TE, et al: Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No 3. JAMA Ophthalmol 2014;132:142-149.
9.
Packer L: Antioxidant action of carotenoids in vitro and in vivo and protection against oxidation of human low-density lipoproteins. Ann NY Acad Sci 1993;691:48-60.
10.
Bohm F, Tinkler JH, Truscott TG: Carotenoids protect against cell membrane damage by the nitrogen dioxide radical. Nat Med 1995;1:98-99.
11.
Hammond BR Jr, Curran-Celentano J, Judd S, et al: Sex differences in macular pigment optical density: relation to plasma carotenoid concentrations and dietary patterns. Vision Res 1996;36:2001-2012.
12.
Hammond BR Jr, Wooten BR, Snodderly DM: Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vision Res 1996;36:3003-3009.
13.
Hammond BR Jr, Fuld K, Snodderly DM: Iris color and macular pigment optical density. Exp Eye Res 1996;62:293-297.
14.
Hammond BR Jr, Wooten BR, Snodderly DM: Density of the human crystalline lens is related to the macular pigment carotenoids, lutein and zeaxanthin. Optom Vis Sci 1997;74:499-504.
15.
Berendschot TT, Willemse-Assink JJ, Bastiaanse M, et al: Macular pigment and melanin in age-related maculopathy in a general population. Invest Ophthalmol Vis Sci 2002;43:1928-1932.
16.
Landrum JT, Bone RA, Kilburn MD: The macular pigment: a possible role in protection from age-related macular degeneration. Adv Pharmacol 1997;38:537-556.
17.
Bone RA, Landrum JT, Mayne ST, et al: Macular pigment in donor eyes with and without AMD: a case-control study. Invest Ophthalmol Vis Sci 2001;42:235-240.
18.
Beatty S, Murray IJ, Henson DB, et al: Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population. Invest Ophthalmol Vis Sci 2001;42:439-446.
19.
Holz FG, Bellman C, Staudt S, et al: Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 2001;42:1051-1056.
20.
Kennedy CJ, Rakoczy PE, Constable IJ: Lipofuscin of the retinal pigment epithelium: a review. Eye 1995;9:763-771.
21.
Lamb TD, Pugh EN Jr: Dark adaptation and the retinoid cycle of vision. Prog Retin Eye Res 2004;23:307-380.
22.
Weng J, Mata NL, Azarian SM, et al: Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 1999;98:13-23.
23.
Beharry S, Zhong M, Molday RS: N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR). J Biol Chem 2004;279:53972-53979.
24.
Rattner A, Smallwood PM, Nathans J: Identification and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol. J Biol Chem 2000;275:11034-11043.
25.
Maeda A, Maeda T, Imanishi Y, et al: Retinol dehydrogenase (RDH12) protects photoreceptors from light-induced degeneration in mice. J Biol Chem 2006;281:37697-37704.
26.
Imanishi Y, Batten ML, Piston DW, et al: Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J Cell Biol 2004;164:373-383.
27.
Imanishi Y, Gerke V, Palczewski K: Retinosomes: new insights into intracellular managing of hydrophobic substances in lipid bodies. J Cell Biol 2004;166:447-453.
28.
Redmond TM, Poliakov E, Yu S, et al: Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci USA 2005;102:13658-13663.
29.
Jin M, Li S, Moghrabi WN, et al: RPE65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 2005;122:449-459.
30.
Moiseyev G, Chen Y, Takahashi Y, et al: RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci USA 2005;102:12413-12418.
31.
Jang GF, Van Hooser JP, Kuksa V, et al: Characterization of a dehydrogenase activity responsible for oxidation of 11-cis-retinol in the retinal pigment epithelium of mice with a disrupted RDH5 gene. A model for the human hereditary disease fundus albipunctatus. J Biol Chem 2001;276:32456-465.
32.
Farjo KM, Moiseyev G, Takahashi Y, et al: The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins. Invest Ophthalmol Vis Sci 2009;50:5089-5097.
33.
Sparrow JR, Fishkin N, Zhou J, et al: A2E, a byproduct of the visual cycle. Vision Res 2003;43:2983-2990.
34.
Radu RA, Han Y, Bui TV, et al: Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci 2005;46:4393-4401.
35.
Kuksa V, Imanishi Y, Batten M, et al: Retinoid cycle in the vertebrate retina: experimental approaches and mechanisms of isomerization. Vision Res 2003;43:2959-2981.
36.
Quadro L, Blaner WS, Salchow DJ, et al: Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J 1999;18:4633-4644.
37.
Vogel S, Piantedosi R, O'Byrne SM, et al: Retinol-binding protein-deficient mice: biochemical basis for impaired vision. Biochemistry 2002;41:15360-15368.
38.
Mata NL, Lichter JB, Vogel R, et al: Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina 2013;33:498-507.
39.
Sieving PA, Chaudhry P, Kondo M, et al: Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci USA 2001;98:1835-1840.
40.
Radu RA, Mata NL, Nusinowitz S, et al: Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci USA 2003;100:4742-4747.
41.
Maeda A, Maeda T, Golczak M, et al: Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice. Mol Pharmacol 2006;70:1220-1229.
42.
Akula JD, Hansen RM, Tzekov R, et al: Visual cycle modulation in neurovascular retinopathy. Exp Eye Res 2010;91:153-161.
43.
Kubota R, Boman NL, David R, et al: Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator. Retina 2012;32:183-188.
44.
Anderson DH, Mullins RF, Hageman GS, et al: A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411-431.
45.
Gehrs KM, Jackson JR, Brown EN, et al: Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol 2010;128:349-358.
46.
Cherepanoff S, McMenamin P, Gillies MC, et al: Bruch's membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol 2010;94:918-925.
47.
Johnson LV, Leitner WP, Staples MK, et al: Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 2001;73:887-896.
48.
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 USA 2005;102:7227-7232.
49.
Klein RJ, Zeiss C, Chew EY, et al: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-389.
50.
Edwards AO, Ritter R 3rd, Abel KJ, et al: Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421-424.
51.
Haines JL, Hauser MA, Schmidt S, et al: Complement factor H variant increases the risk of age-related macular degeneration. Science 2005;308:419-421.
52.
Hughes AE, Orr N, Esfandiary H, et al: A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 2006;38:1173-1177.
53.
Skerka C, Lauer N, Weinberger AA, et al: Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 2007;44:3398-3406.
54.
Magnusson KP, Duan S, Sigurdsson H, et al: CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS Med 2006;3:e5.
55.
Li M, Atmaca-Sonmez P, Othman M, et al: CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 2006;38:1049-1054.
56.
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;38:458-462.
57.
Spencer KL, Hauser MA, Olson LM, et al: Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet 2007;16:1986-1992.
58.
Yates JR, Sepp T, Matharu BK, et al: Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 2007;357:553-561.
59.
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;372:1828-1834.
60.
Maller JB, Fagerness JA, Reynolds RC, et al: Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007;39:1200-1201.
61.
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;17:100-104.
62.
Thurman JM, Holers VM: The central role of the alternative complement pathway in human disease. J Immunol 2006;176:1305-1310.
63.
Sohn JH, Kaplan HJ, Suk HJ, et al: Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest Ophthalmol Vis Sci 2000;41:3492-3502.
64.
Thurman JM, Renner B, Kunchithapautham K, et al: Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem 2009;284:16939-16947.
65.
Wu Z, Lauer TW, Sick A, et al: Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3. J Biol Chem 2007;282:22414-22425.
66.
Zhou J, Jang YP, Kim SR, et al: Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci USA 2006;103:16182-16187.
67.
Engelbert M, Gilmore MS: Fas ligand but not complement is critical for control of experimental Staphylococcus aureus endophthalmitis. Invest Ophthalmol Vis Sci 2005;46:2479-2486.
68.
Giese MJ, Mondino BJ, Glasgow BJ, et al: Complement system and host defense against staphylococcal endophthalmitis. Invest Ophthalmol Vis Sci 1994;35:1026-1032.
69.
Aizuss DH, Mondino BJ, Sumner HL, et al: The complement system and host defense against Pseudomonas endophthalmitis. Invest Ophthalmol Vis Sci 1985;26:1262-1266.
70.
Yehoshua Z, Alexandre de Amorim Garcia Filho C, Nunes RP, et al: Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology 2014;121:693-701.
71.
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;45:1366-1370.
72.
Regillo CD: Lampalizumab (anti-factor D) in patients with geography atrophy: the MAHALO phase II results. Presented at the 2013 Ann Meet Am Acad Ophthalmol, New Orleans, November 2013.
73.
Wong WT, Dresner S, Forooghian F, et al: Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2013;54:2941-2950.
74.
Landa G, Butovsky O, Shoshani J, et al: Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related macular degeneration. Curr Eye Res 2008;33:1011-1013.
75.
Johnson LV, Leitner WP, Rivest AJ, et al: The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci USA 2002;99:11830-11835.
76.
Isas JM, Luibl V, Johnson LV, et al: Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci 2010;51:1304-1310.
77.
Wang J, Ohno-Matsui K, Yoshida T, et al: Amyloid-β up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration. J Cell Physiol 2009;220:119-128.
78.
Ding JD, Johnson LV, Herrmann R, et al: Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. Proc Natl Acad Sci USA 2011;108:E279-E287.
79.
Catchpole I, Germaschewski V, Hoh Kam J, et al: Systemic administration of A-beta mAb reduces retinal deposition of A-beta and activated complement C3 in age-related macular degeneration mouse model. PLoS One 2013;8:e65518.
80.
Grunwald JE, Hariprasad SM, DuPont J: Effect of aging on foveolar choroidal circulation. Arch Ophthalmol 1998;116:150-154.
81.
Grunwald JE, Metelitsina TI, Dupont JC, et al: Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci 2005;46:1033-1008.
82.
Boltz A, Luksch A, Wimpissinger B, et al: Choroidal blood flow and progression of age-related macular degeneration in the fellow eye in patients with unilateral choroidal neovascularization. Invest Ophthalmol Vis Sci 2010;51:4220-4225.
83.
Ralston PG, Sloan D, Waters-Honcu D, Saigal S, Torkildsen G: A pilot, open-label study of the safety of MC-1101 in both normal volunteers and patients with early nonexudative age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:E-Abstract 913.
84.
Dunaief JL, Dentchev T, Ying GS, et al: The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 2002;120:1435-1442.
85.
Li Y, Tao W, Luo L, et al: CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One 2010;5:e9495.
86.
Tao W, Wen R, Goddard MB, et al: Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci 2002;43:3292-3298.
87.
Zhang K, Hopkins JJ, Heier JS, et al: Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci USA 2011;108:6241-6245.
88.
Bok D, Yasumura D, Matthes MT, et al: Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation. Exp Eye Res 2002;74:719-735.
89.
Zeiss CJ, Allore HG, Towle V, et al: CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retina. Exp Eye Res 2006;82:395-404.
90.
Lai RK, Chun T, Hasson D, et al: Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Vis Neurosci 2002;19:175-185.
91.
WoldeMussie E, Ruiz G, Wijono M, et al: Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci 2001;42:2849-2855.
92.
Wheeler L, WoldeMussie E, Lai R: Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol 2003;48(suppl 1):S47-S51.
93.
Tatton W, Chen D, Chalmers-Redman R, et al: Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer's disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Surv Ophthalmol 2003;48(suppl 1):S25-S37.
94.
Zarbin M: The promise of stem cells for age-related macular degeneration and other retinal degenerative diseases. Drug Discov Today Ther Strateg 2012.
95.
Melville H, Carpiniello M, Hollis K, et al: Stem cells: a new paradigm for disease modeling and developing therapies for age-related macular degeneration. J Transl Med 2013;11:53.
96.
Sarks JP, Sarks SH, Killingsworth MC: Evolution of geographic atrophy of the retinal pigment epithelium. Eye (Lond) 1988;2:552-577.
97.
Zhu D, Wu J, Spee C, et al: BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem 2009;284:9529-9539.
98.
Shen JK, Dong A, Hackett SF, et al: Oxidative damage in age-related macular degeneration. Histol Histopathol 2007;22:1301-1308.
99.
Casaroli-Marano RP, Zarbin MA: Cell-Based Therapy for Retinal Degenerative Disease. Basel, Karger, 2014.
100.
Carr AJ, Vugler AA, Hikita ST, et al: Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One 2009;4:e8152.
101.
Sugino IK, Sun Q, Wang J, et al: Comparison of FRPE and human embryonic stem cell-derived RPE behavior on aged human Bruch's membrane. Invest Ophthalmol Vis Sci 2011;52:4979-4997.
102.
Schwartz SD, Hubschman JP, Heilwell G, et al: Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012;379:713-720.
103.
Sugino IK, Rapista A, Sun Q, et al: A method to enhance cell survival on Bruch's membrane in eyes affected by age and age-related macular degeneration. Invest Ophthalmol Vis Sci 2011;52:9598-9609.
104.
Jones BW, Watt CB, Frederick JM, et al: Retinal remodeling triggered by photoreceptor degenerations. J Comp Neurol 2003;464:1-16.
105.
Fairchild PJ: The challenge of immunogenicity in the quest for induced pluripotency. Nat Rev Immunol 2010;10:868-875.
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