Review of emerging treatments for age-related macular degeneration

Studies on Retinal and Choroidal Disorders

Volumn , Issue , 2012, Pages 1-46

  Zarbin, Marco A ^a   Rosenfeld, Philip J ^b  

^a INSTITUTE OF OPHTHALMOLOGY AND VISUAL SCIENCE   (United States)

^b UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84925853657     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-61779-606-7_1     Document Type: Chapter

References (273)

1. Friedman DS, O'Colmain BJ, Munoz B et al (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122:564-572.
2. Zarbin MA (2004) Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 122:598-614.
3. Zarbin M, Sunness JS (2010) Dry age-related macular degeneration and age-related macular degeneration pathogenesis. In: Levin LA, Albert DM (eds) Ocular disease: mechanisms and management. Saunders, Philadelphia, pp 527-535.
4. Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP (2005) Smoking and age-related macular degeneration: a review of association. Eye 19:935-944.
5. Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med 58:295-300.
6. Susser M (1991) What is a cause and how do we know one? A grammar for pragmatic epidemiology. Am J Epidemiol 133:635-648.
7. Hammond BR Jr, Wooten BR, Snodderly DM (1996) Cigarette smoking and retinal carotenoids:implications for age-related macular degeneration. Vision Res 36:3003-3009.
8. Solberg Y, Rosner M, Belkin M (1998) The association between cigarette smoking and ocular diseases. Surv Ophthalmol 42:535-547.
9. Fusby JS, Kassmeier MD, Palmer VL et al (2010) Cigarette smoke-induced effects on bone marrow B-cell subsets and CD4+:CD8+ T-cell ratios are reversed by smoking cessation: influence of bone mass on immune cell response to and recovery from smoke exposure. Inhal Toxicol 22:785-796.
10. Suner IJ, Espinosa-Heidmann DG, Marin-Castano ME, Hernandez EP, Pereira-Simon S, Cousins SW (2004) Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 45:311-317.
11. Rahman I, MacNee W (1996) Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med 21:669-681.
12. Mitchell P, Wang JJ, Smith W, Leeder SR (2002) Smoking and the 5-year incidence of agerelated maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 120:1357-1363.
13. Fujihara M, Nagai N, Sussan TE, Biswal S, Handa JT (2008) Chronic cigarette smoke causes oxidative damage and apoptosis to retinal pigmented epithelial cells in mice. PLoS One 3:e3119.
14. Cano M, Thimmalappula R, Fujihara M et al (2010) Cigarette smoking, oxidative stress, the anti-oxidant response through Nrf2 signaling, and age-related macular degeneration. Vision Res 50:652-664.
15. Green WR, McDonnell PJ, Yeo JH (1985) Pathologic features of senile macular degeneration. Ophthalmology 92:615-627.
16. Harman AM, Fleming PA, Hoskins RV, Moore SR (1997) Development and aging of cell topography in the human retinal pigment epithelium. Invest Ophthalmol Vis Sci 38:2016-2026.
17. Dunaief JL, Dentchev T, Ying GS, Milam AH (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120:1435-1442.
18. Group Age Related Eye Disease Study Research (2001) 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 119:1417-1436.
19. Moriarty-Craige SE, Adkison J, Lynn M et al (2005) Antioxidant supplements prevent oxidation of cysteine/cystine redox in patients with age-related macular degeneration. Am J Ophthalmol 140:1020-1026.
20. Prasad AS (2008) Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontol 43:370-377.
21. Klein ML, Francis PJ, Rosner B et al (2008) CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115:1019-1025.
22. Canter JA, Olson LM, Spencer K et al (2008) Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoS One 3:e2091.
23. Kimura K, Isashiki Y, Sonoda S, Kakiuchi-Matsumoto T, Ohba N (2000) Genetic association of manganese superoxide dismutase with exudative age-related macular degeneration. Am J Ophthalmol 130:769-773.
24. Conley YP, Jakobsdottir J, Mah T et al (2006) CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and metaanalyses. Hum Mol Genet 15:3206-3218.
25. Kanda A, Chen W, Othman M et al (2007) A variant of mitochondrial protein LOC387715/ ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA 104:16227-16232.
26. Wang G, Spencer KL, Court BL et al (2009) Localization of age-related macular degenerationassociated ARMS2 in cytosol, not mitochondria. Invest Ophthalmol Vis Sci 50:3084-3090.
27. Shen JK, Dong A, Hackett SF, Bell WR, Green WR, Campochiaro PA (2007) Oxidative damage in age-related macular degeneration. Histol Histopathol 22:1301-1308.
28. Frank RN, Amin RH, Puklin JE (1999) Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration. Am J Ophthalmol 127:694-709.
29. Ishibashi K, Tian J, Handa JT (2004) Similarity of mRNA phenotypes of morphologically normal macular and peripheral retinal pigment epithelial cells in older human eyes. Invest Ophthalmol Vis Sci 45:3291-3301.
30. Crabb JW, Miyagi M, Gu X et al (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99:14682-14687.
31. Ishibashi T, Murata T, Hangai M et al (1998) Advanced glycation end products in age-related macular degeneration. Arch Ophthalmol 116:1629-1632.
32. Hammes HP, Hoerauf H, Alt A et al (1999) N(epsilon)(carboxymethyl)lysin and the AGE receptor RAGE colocalize in age-related macular degeneration. Invest Ophthalmol Vis Sci 40:1855-1859.
33. He X, Hahn P, Iacovelli J et al (2007) Iron homeostasis and toxicity in retinal degeneration. Prog Retin Eye Res 26:649-673.
34. Hahn P, Milam AH, Dunaief JL (2003) Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch's membrane. Arch Ophthalmol 121:1099-1105.
35. Nordgaard CL, Berg KM, Kapphahn RJ et al (2006) Proteomics of the retinal pigment epithelium reveals altered protein expression at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci 47:815-822.
36. Decanini A, Nordgaard CL, Feng X, Ferrington DA, Olsen TW (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143:607-615.
37. Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE (2001) Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 42:1051-1056.
38. Kennedy CJ, Rakoczy PE, Constable IJ (1995) Lipofuscin of the retinal pigment epithelium: a review. Eye 9(Pt 6):763-771.
39. Lamb TD, Pugh EN Jr (2004) Dark adaptation and the retinoid cycle of vision. Prog Retin Eye Res 23:307-380.
40. Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH (1999) Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 98:13-23.
41. Beharry S, Zhong M, Molday RS (2004) N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR). J Biol Chem 279:53972-53979.
42. Rattner A, Smallwood PM, Nathans J (2000) Identification and characterization of all-transretinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol. J Biol Chem 275:11034-11043.
43. Maeda A, Maeda T, Imanishi Y et al (2006) Retinol dehydrogenase (RDH12) protects photoreceptors from light-induced degeneration in mice. J Biol Chem 281:37697-37704.
44. Imanishi Y, Batten ML, Piston DW, Baehr W, Palczewski K (2004) Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J Cell Biol 164:373-383.
45. Imanishi Y, Gerke V, Palczewski K (2004) Retinosomes: new insights into intracellular managing of hydrophobic substances in lipid bodies. J Cell Biol 166:447-453.
46. Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S (2005) Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci USA 102:13658-13663.
47. Jin M, Li S, Moghrabi WN, Sun H, Travis GH (2005) Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 122:449-459.
48. Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX (2005) RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci USA 102:12413-12418.
49. Jang GF, Van Hooser JP, Kuksa V et al (2001) 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 276:32456-32465.
50. Farjo KM, Moiseyev G, Takahashi Y, Crouch RK, Ma JX (2009) The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins. Invest Ophthalmol Vis Sci 50:5089-5097.
51. Sparrow JR, Fishkin N, Zhou J et al (2003) A2E, a byproduct of the visual cycle. Vision Res 43:2983-2990.
52. Anderson DH, Mullins RF, Hageman GS, Johnson LV (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134:411-431.
53. Hageman GS, Anderson DH, Johnson LV et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102:7227-7232.
54. Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 73:887-896.
55. Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) 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 14:835-846.
56. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20:705-732.
57. Nozaki M, Raisler BJ, Sakurai E et al (2006) Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA 103:2328-2333.
58. Patel M, Chan CC (2008) Immunopathological aspects of age-related macular degeneration. Semin Immunopathol 30:97-110.
59. Penfold PL, Madigan MC, Gillies MC, Provis JM (2001) Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 20:385-414.
60. Blom AM, Kask L, Ramesh B, Hillarp A (2003) Effects of zinc on factor I cofactor activity of C4b-binding protein and factor H. Arch Biochem Biophys 418:108-118.
61. Sivaprasad S, Adewoyin T, Bailey TA et al (2007) Estimation of systemic complement C3 activity in age-related macular degeneration. Arch Ophthalmol 125:515-519.
62. Prasad AS (2009) Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care 12:646-652.
63. Prasad AS, Meftah S, Abdallah J et al (1988) Serum thymulin in human zinc deficiency. J Clin Invest 82:1202-1210.
64. Beck FW, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ (1997) Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol 272:E1002-E1007.
65. Biswas SK, Rahman I (2009) Environmental toxicity, redox signaling and lung inflammation:the role of glutathione. Mol Aspects Med 30:60-76.
66. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196-5203.
67. Thimmulappa RK, Lee H, Rangasamy T et al (2006) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116:984-995.
68. Nagai N, Thimmulappa RK, Cano M et al (2009) Nrf2 is a critical modulator of the innate immune response in a model of uveitis. Free Radic Biol Med 47:300-306.
69. Braun S, Hanselmann C, Gassmann MG et al (2002) Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Mol Cell Biol 22:5492-5505.
70. Li J, Stein TD, Johnson JA (2004) Genetic dissection of systemic autoimmune disease in Nrf2- deficient mice. Physiol Genomics 18:261-272.
71. Wang AL, Lukas TJ, Yuan M, Du N, Handa JT, Neufeld AH (2009) Changes in retinal pigment epithelium related to cigarette smoke: possible relevance to smoking as a risk factor for agerelated macular degeneration. PLoS One 4:e5304.
72. Gao X, Talalay P (2004) Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage. Proc Natl Acad Sci USA 101:10446-10451.
73. Nelson KC, Armstrong JS, Moriarty S et al (2002) Protection of retinal pigment epithelial cells from oxidative damage by oltipraz, a cancer chemopreventive agent. Invest Ophthalmol Vis Sci 43:3550-3554.
74. Nelson KC, Carlson JL, Newman ML et al (1999) Effect of dietary inducer dimethylfumarate on glutathione in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 40:1927-1935.
75. Ha KN, Chen Y, Cai J, Sternberg P Jr (2006) Increased glutathione synthesis through an ARENrf2- dependent pathway by zinc in the RPE: implication for protection against oxidative stress. Invest Ophthalmol Vis Sci 47:2709-2715.
76. Suh JH, Shenvi SV, Dixon BM et al (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci USA 101:3381-3386.
77. Dinkova-Kostova AT, Liby KT, Stephenson KK et al (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102:4584-4589.
78. Kong L, Tanito M, Huang Z et al (2007) Delay of photoreceptor degeneration in tubby mouse by sulforaphane. J Neurochem 101:1041-1052.
79. Tanito M, Masutani H, Kim YC, Nishikawa M, Ohira A, Yodoi J (2005) Sulforaphane induces thioredoxin through the antioxidant-responsive element and attenuates retinal light damage in mice. Invest Ophthalmol Vis Sci 46:979-987.
80. Wang L, Chen Y, Sternberg P, Cai J (2008) Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest Ophthalmol Vis Sci 49:1671-1678.
81. Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357-369.
82. Liby K, Hock T, Yore MM et al (2005) The synthetic triterpenoids, CDDO and CDDOimidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 65:4789-4798.
83. Yates MS, Tauchi M, Katsuoka F et al (2007) Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther 6:154-162.
84. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428-435.
85. Xu H, Chen M, Forrester JV (2009) Para-inflammation in the aging retina. Prog Retin Eye Res 28:348-368.
86. Medzhitov R, Janeway CA Jr (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298-300.
87. Oppenheim JJ, Dong HF, Plotz P et al (2005) Autoantigens act as tissue-specific chemoattractants. J Leukoc Biol 77:854-861.
88. Oppenheim JJ, Yang D (2005) Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 17:359-365.
89. McGeer PL, McGeer EG (2004) Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci 1035:104-116.
90. Shen Y, Meri S (2003) Yin and Yang: complement activation and regulation in Alzheimer's disease. Prog Neurobiol 70:463-472.
91. Cosentino F, Francia P, Musumeci B et al (2006) Nitric oxide release is impaired in hypertensive individuals with familial history of stroke. Am J Hypertens 19:1213-1216.
92. Vohra RS, Murphy JE, Walker JH, Ponnambalam S, Homer-Vanniasinkam S (2006) Atherosclerosis and the lectin-like oxidized low-density lipoprotein scavenger receptor. Trends Cardiovasc Med 16:60-64.
93. Chen M, Muckersie E, Robertson M, Forrester JV, Xu H (2008) Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res 87:543-550.
94. Chen M, Forrester JV, Xu H (2007) Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res 84:635-645.
95. Fernandes AF, Zhou J, Zhang X et al (2008) Oxidative inactivation of the proteasome in retinal pigment epithelial cells. A potential link between oxidative stress and up-regulation of interleukin-8. J Biol Chem 283:20745-20753.
96. Higgins GT, Wang JH, Dockery P, Cleary PE, Redmond HP (2003) Induction of angiogenic cytokine expression in cultured RPE by ingestion of oxidized photoreceptor outer segments. Invest Ophthalmol Vis Sci 44:1775-1782.
97. Hageman GS, Hancox LS, Taiber AJ et al (2006) Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 38:592-604.
98. Anderson DH, Radeke MJ, Gallo NB et al (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29:95-112.
99. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 38:1173-1177.
100. Klein RJ, Zeiss C, Chew EY et al (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385-389.
101. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421-424.
102. Haines JL, Hauser MA, Schmidt S et al (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419-421.
103. Skerka C, Lauer N, Weinberger AA et al (2007) Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 44:3398-3406.
104. Magnusson KP, Duan S, Sigurdsson H et al (2006) CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS Med 3:e5.
105. Li M, Atmaca-Sonmez P, Othman M et al (2006) CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 38:1049-1054.
106. Gold B, Merriam JE, Zernant J et al (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38:458-462.
107. Spencer KL, Hauser MA, Olson LM et al (2007) Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet 16:1986-1992.
108. Yates JR, Sepp T, Matharu BK et al (2007) Complement C3 variant and the risk of agerelated macular degeneration. N Engl J Med 357:553-561.
109. Ennis S, Jomary C, Mullins R et al (2008) Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet 372:1828-1834.
110. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM (2007) Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 39:1200-1201.
111. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM (2009) Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 17:100-104.
112. Heinen S, Hartmann A, Lauer N et al (2009) Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114:2439-2447.
113. Thurman JM, Holers VM (2006) The central role of the alternative complement pathway in human disease. J Immunol 176:1305-1310.
114. Sohn JH, Kaplan HJ, Suk HJ, Bora PS, Bora NS (2000) Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest Ophthalmol Vis Sci 41:3492-3502.
115. Thurman JM, Renner B, Kunchithapautham K et al (2009) Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem 284:16939-16947.
116. Wu Z, Lauer TW, Sick A, Hackett SF, Campochiaro PA (2007) Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3. J Biol Chem 282:22414-22425.
117. Zhou J, Jang YP, Kim SR, Sparrow JR (2006) Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci USA 103:16182-16187.
118. Hollyfield JG, Bonilha VL, Rayborn ME et al (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194-198.
119. Dewan A, Liu M, Hartman S et al (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314:989-992.
120. Rivera A, Fisher SA, Fritsche LG et al (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14:3227-3236.
121. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB (2005) Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77:389-407.
122. Schmidt S, Hauser MA, Scott WK et al (2006) Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 78:852-864.
123. Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, Sue CM (2007) Mitochondrial DNA haplogroups and age-related maculopathy. Arch Ophthalmol 125:1235-1240.
124. Sobrin L, Reynolds R, Yu Y et al (2011) ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration. Am J Ophthalmol 151(345-52):e3.
125. Seddon JM, Gensler G, Rosner B (2010) C-reactive protein and CFH, ARMS2/HTRA1 gene variants are independently associated with risk of macular degeneration. Ophthalmology 117:1560-1566.
126. Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH (2009) Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and agerelated macular degeneration. PLoS One 4:e4160.
127. Jones M, Mitchell P, Wang JJ, Sue C (2004) MELAS A3243G mitochondrial DNA mutation and age related maculopathy. Am J Ophthalmol 138:1051-1053.
128. Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco GC (2006) Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging 27:983-993.
129. Jarrett SG, Lin H, Godley BF, Boulton ME (2008) Mitochondrial DNA damage and its potential role in retinal degeneration. Prog Retin Eye Res 27:596-607.
130. Miceli MV, Liles MR, Newsome DA (1994) Evaluation of oxidative processes in human pigment epithelial cells associated with retinal outer segment phagocytosis. Exp Cell Res 214:242-249.
131. Jin GF, Hurst JS, Godley BF (2001) Rod outer segments mediate mitochondrial DNA damage and apoptosis in human retinal pigment epithelium. Curr Eye Res 23:11-19.
132. Liang FQ, Godley BF (2003) Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res 76:397-403.
133. Wei YH (1998) Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med 217:53-63.
134. Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 94:514-519.
135. Vives-Bauza C, Anand M, Shirazi AK et al (2008) The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells. J Biol Chem 283:24770-24780.
136. Liang LP, Patel M (2004) Iron-sulfur enzyme mediated mitochondrial superoxide toxicity in experimental Parkinson's disease. J Neurochem 90:1076-1084.
137. Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO (1996) Requirement for superoxide in excitotoxic cell death. Neuron 16:345-355.
138. -•), superoxide dismutases, and related matters. J Biol Chem 272:18515-18517.
139. Armstrong JS (2007) Mitochondrial medicine: pharmacological targeting of mitochondria in disease. Br J Pharmacol 151:1154-1165.
140. Jauslin ML, Meier T, Smith RA, Murphy MP (2003) Mitochondria-targeted antioxidants protect Friedreich ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J 17:1972-1974.
141. Tauskela JS (2007) MitoQ-a mitochondria-targeted antioxidant. IDrugs 10:399-412.
142. Weissig V, Boddapati SV, Jabr L, D'Souza GG (2007) Mitochondria-specific nanotechnology. Nanomedicine (Lond) 2:275-285.
143. Meister G (2011) Vision: dicer leaps into view. Nature 471:308-309.
144. Kaneko H, Dridi S, Tarallo V et al (2011) DICER1 deficit induces Alu RNA toxicity in agerelated macular degeneration. Nature 471:325-330.
145. Zhu D, Wu J, Spee C, Ryan SJ, Hinton DR (2009) BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem 284:9529-9539.
146. Yu AL, Fuchshofer R, Kook D, Kampik A, Bloemendal H, Welge-Lussen U (2009) Subtoxic oxidative stress induces senescence in retinal pigment epithelial cells via TGF-beta release. Invest Ophthalmol Vis Sci 50:926-935.
147. Zhu D, Deng X, Xu J, Hinton DR (2009) What determines the switch between atrophic and neovascular forms of age related macular degeneration?-the role of BMP4 induced senescence. Aging (Albany NY) 1:740-745.
148. Zarbin MA, Rosenfeld PJ (2010) Pathway-based therapies for age-related macular degeneration:an integrated survey of emerging treatment alternatives. Retina 30:1350-1367.
149. Reading VM, Weale RA (1974) Macular pigment and chromatic aberration. J Opt Soc Am 64:231-234.
150. Packer L (1993) Antioxidant action of carotenoids in vitro and in vivo and protection against oxidation of human low-density lipoproteins. Ann N Y Acad Sci 691:48-60.
151. Bohm F, Tinkler JH, Truscott TG (1995) Carotenoids protect against cell membrane damage by the nitrogen dioxide radical. Nat Med 1:98-99.
152. Hammond BR Jr, Curran-Celentano J, Judd S et al (1996) Sex differences in macular pigment optical density: relation to plasma carotenoid concentrations and dietary patterns. Vision Res 36:2001-2012.
153. Loane E, Nolan JM, Beatty S (2010) The respective relationships between lipoprotein profile, macular pigment optical density and serum concentrations of lutein and zeaxanthin. Invest Ophthalmol Vis Sci 51:5897-5905.
154. Bone RA, Landrum JT, Fernandez L, Tarsis SL (1988) Analysis of the macular pigment by HPLC: retinal distribution and age study. Invest Ophthalmol Vis Sci 29:843-849.
155. Tan JS, Wang JJ, Flood V, Rochtchina E, Smith W, Mitchell P (2008) Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology 115:334-341.
156. Parisi V, Tedeschi M, Gallinaro G, Varano M, Saviano S, Piermarocchi S (2008) Carotenoids and antioxidants in age-related maculopathy Italian study: multifocal electroretinogram modifications after 1 year. Ophthalmology 115(324-333):e2.
157. Cho E, Hankinson SE, Rosner B, Willett WC, Colditz GA (2008) Prospective study of lutein/ zeaxanthin intake and risk of age-related macular degeneration. Am J Clin Nutr 87:1837-1843.
158. SanGiovanni JP, Chew EY (2005) The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res 24:87-138.
159. Chong EW, Kreis AJ, Wong TY, Simpson JA, Guymer RH (2008) Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol 126:826-833.
160. Chong EW, Wong TY, Kreis AJ, Simpson JA, Guymer RH (2007) Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis. BMJ 335:755.
161. Radu RA, Han Y, Bui TV et al (2005) 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 46:4393-4401.
162. Quadro L, Blaner WS, Salchow DJ et al (1999) Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J 18:4633-4644.
163. Vogel S, Piantedosi R, O'Byrne SM et al (2002) Retinol-binding protein-deficient mice:biochemical basis for impaired vision. Biochemistry 41:15360-15368.
164. Decensi A, Torrisi R, Bruno S et al (2000) Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate end point. Cancer Epidemiol Biomarkers Prev 9:1071-1078.
165. Follen M, Atkinson EN, Schottenfeld D et al (2001) A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix. Clin Cancer Res 7:3356-3365.
166. Camerini T, Mariani L, De Palo G et al (2001) Safety of the synthetic retinoid fenretinide:long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 19:1664-1670.
167. Garaventa A, Luksch R, Lo Piccolo MS et al (2003) Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma. Clin Cancer Res 9:2032-2039.
168. Puduvalli VK, Yung WK, Hess KR et al (2004) Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol 22:4282-4289.
169. Mariani L, Formelli F, De Palo G et al (1996) Chemoprevention of breast cancer with fenretinide (4-HPR): study of long-term visual and ophthalmologic tolerability. Tumori 82:444-449.
170. Conley B, O'Shaughnessy J, Prindiville S et al (2000) Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer. J Clin Oncol 18:275-283.
171. Caruso RC, Zujewski J, Iwata F et al (1998) Effects of fenretinide (4-HPR) on dark adaptation. Arch Ophthalmol 116:759-763.
172. Kaiser-Kupfer MI, Peck GL, Caruso RC, Jaffe MJ, DiGiovanna JJ, Gross EG (1986) Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Ophthalmol 104:69-70.
173. Decensi A, Torrisi R, Polizzi A et al (1994) Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. J Natl Cancer Inst 86:105-110.
174. Decensi A, Fontana V, Fioretto M et al (1997) Long-term effects of fenretinide on retinal function. Eur J Cancer 33:80-84.
175. Marmor MF, Jain A, Moshfeghi D (2008) Total rod ERG suppression with high dose compassionate fenretinide usage. Doc Ophthalmol 117:257-261.
176. Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH (2003) Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci USA 100:4742-4747.
177. Sieving PA, Chaudhry P, Kondo M et al (2001) 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 98:1835-1840.
178. Kubota R, Boman NL, David R, Mallikaarjun S, Patil S, Birch D. Safety and effect on rod function of acu-4429, a novel small-molecule visual cycle modulator. Retina 2012;32:183-8.
179. Masland RH (2001) The fundamental plan of the retina. Nat Neurosci 4:877-886.
180. Zarbin M (2006) Should corticosteroids be considered as part of the standard care with photodynamic therapy? Arch Ophthalmol 124:563-571.
181. Engelbert M, Gilmore MS (2005) Fas ligand but not complement is critical for control of experimental Staphylococcus aureus endophthalmitis. Invest Ophthalmol Vis Sci 46:2479-2486.
182. Giese MJ, Mondino BJ, Glasgow BJ et al (1994) Complement system and host defense against staphylococcal endophthalmitis. Invest Ophthalmol Vis Sci 35:1026-1032.
183. Aizuss DH, Mondino BJ, Sumner HL, Dethlefs BA (1985) The complement system and host defense against Pseudomonas endophthalmitis. Invest Ophthalmol Vis Sci 26:1262-1266.
184. Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, Tong Z, Chen H, Constantine R et al (2008) Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 359(14):1456-1463. doi: 10.1056/NEJMoa0802437.
185. Schmid-Kubista KE, Tosakulwong N, Wu Y et al (2009) Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci 50:5070-5079.
186. Landa G, Butovsky O, Shoshani J, Schwartz M, Pollack A (2008) Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related macular degeneration. Curr Eye Res 33:1011-1013.
187. Complications of Age-Related Macular Degeneration Prevention Trial Research Group (2006) Laser treatment in patients with bilateral large drusen: the complications of agerelated macular degeneration prevention trial. Ophthalmology 113:1974-1986.
188. Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH (2002) The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A 99:11830-11835.
189. Isas JM, Luibl V, Johnson LV et al (2010) Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci 51:1304-1310.
190. Wang J, Ohno-Matsui K, Yoshida T et al (2009) Amyloid-beta 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 220:119-128.
191. Catchpole IR, Germaschewski V, Ford S, Gough G, Overend P, Adamson P, Lundh von Leithner P, Kam JH, Coffey P, Jeffery G (2011) Systemic administration of an anti-amyloid beta monoclonal antibody interferes with the ocular pathology of a mouse model of agerelated macular degeneration (AMD)/retinal dysfunction [poster]. Invest Ophthalmol Vis Sci 52:E-Abstract 1778.
192. Chaum E (2003) Retinal neuroprotection by growth factors: a mechanistic perspective. J Cell Biochem 88:57-75.
193. Wenzel A, Grimm C, Samardzija M, Reme CE (2005) Molecular mechanisms of lightinduced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res 24:275-306.
194. LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH (1992) Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci USA 89:11249-11253.
195. LaVail MM, Yasumura D, Matthes MT et al (1998) Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 39:592-602.
196. Cao W, Tombran-Tink J, Elias R, Sezate S, Mrazek D, McGinnis JF (2001) In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 42:1646-1652.
197. Cayouette M, Smith SB, Becerra SP, Gravel C (1999) Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis 6:523-532.
198. Miyazaki M, Ikeda Y, Yonemitsu Y et al (2003) Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats. Gene Ther 10:1503-1511.
199. Schweigerer LMB, Neufeld G, Gospodarowicz D (1987) Basic fibroblast growth factor is synthesized in cultured retinal pigment epithelial cells. Biochem Biophys Res Commun 143:934-940.
200. Waldbillig RJ, Pfeffer BA, Schoen TJ et al (1991) Evidence for an insulin-like growth factor autocrine-paracrine system in the retinal photoreceptor-pigment epithelial cell complex. J Neurochem 57:1522-1533.
201. Takagi H, Yoshimura N, Tanihara H, Honda Y (1994) Insulin-like growth factor-related genes, receptors, and binding proteins in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 35:916-923.
202. Tombran-Tink J, Barnstable CJ (2003) PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 4:628-636.
203. Wen R, Cheng T, Song Y et al (1998) Continuous exposure to bright light upregulates bFGF and CNTF expression in the rat retina. Curr Eye Res 17:494-500.
204. Campochiaro PA, Chang M, Ohsato M et al (1996) Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor. J Neurosci 16:1679-1688.
205. Cayouette M, Gravel C (1997) Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum Gene Ther 8:423-430.
206. Leveillard T, Mohand-Said S, Lorentz O et al (2004) Identification and characterization of rod-derived cone viability factor. Nat Genet 36:755-759.
207. Chalmel F, Leveillard T, Jaillard C et al (2007) Rod-derived Cone Viability Factor-2 is a novel bifunctional-thioredoxin-like protein with therapeutic potential. BMC Mol Biol 8:74.
208. Machida S, Chaudhry P, Shinohara T et al (2001) Lens epithelium-derived growth factor promotes photoreceptor survival in light-damaged and RCS rats. Invest Ophthalmol Vis Sci 42:1087-1095.
209. Raz-Prag D, Zeng Y, Sieving PA, Bush RA (2009) Photoreceptor protection by adeno-associated virus-mediated LEDGF expression in the RCS rat model of retinal degeneration: probing the mechanism. Invest Ophthalmol Vis Sci 50:3897-3906.
210. Li Y, Roth S, Laser M, Ma JX, Crosson CE (2003) Retinal preconditioning and the induction of heat-shock protein 27. Invest Ophthalmol Vis Sci 44:1299-1304.
211. Yu Q, Kent CR, Tytell M (2001) Retinal uptake of intravitreally injected Hsc/Hsp70 and its effect on susceptibility to light damage. Mol Vis 7:48-56.
212. Wen R, Cheng T, Li Y, Cao W, Steinberg RH (1996) Alpha 2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage. J Neurosci 16:5986-5992.
213. Bok D, Yasumura D, Matthes MT et al (2002) 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 74:719-735.
214. Beltran WA, Allore HG, Johnson E et al (2009) CREB1/ATF1 activation in photoreceptor degeneration and protection. Invest Ophthalmol Vis Sci 50:5355-5363.
215. Wahlin KJ, Campochiaro PA, Zack DJ, Adler R (2000) Neurotrophic factors cause activation of intracellular signaling pathways in Muller cells and other cells of the inner retina, but not photoreceptors. Invest Ophthalmol Vis Sci 41:927-936.
216. Azadi S, Johnson LE, Paquet-Durand F et al (2007) CNTF + BDNF treatment and neuroprotective pathways in the rd1 mouse retina. Brain Res 1129:116-129.
217. Wahlin KJ, Adler R, Zack DJ, Campochiaro PA (2001) Neurotrophic signaling in normal and degenerating rodent retinas. Exp Eye Res 73:693-701.
218. Beltran WA, Rohrer H, Aguirre GD (2005) Immunolocalization of ciliary neurotrophic factor receptor alpha (CNTFRalpha) in mammalian photoreceptor cells. Mol Vis 11:232-244.
219. Allikmets R (2000) Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet 67:487-491.
220. Allikmets R, Shroyer NF, Singh N et al (1997) Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277:1805-1807.
221. Stone EM, Webster AR, Vandenburgh K et al (1998) Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration. Nat Genet 20:328-329.
222. Joseph RM, Li T (1996) Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration. Invest Ophthalmol Vis Sci 37:2434-2446.
223. Nir I, Kedzierski W, Chen J, Travis GH (2000) Expression of Bcl-2 protects against photoreceptor degeneration in retinal degeneration slow (rds) mice. J Neurosci 20:2150-2154.
224. Ranchon I, LaVail MM, Kotake Y, Anderson RE (2003) Free radical trap phenyl-N-tertbutylnitrone protects against light damage but does not rescue P23H and S334ter rhodopsin transgenic rats from inherited retinal degeneration. J Neurosci 23:6050-6057.
225. Organisciak DT, Darrow RM, Barsalou L, Kutty RK, Wiggert B (2003) Susceptibility to retinal light damage in transgenic rats with rhodopsin mutations. Invest Ophthalmol Vis Sci 44:486-492.
226. Lavail MMYD, Matthes MT, Lau-villacorta C, Unoki K, Sung C-H, Steinberg RH (1998) Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 39:592-602.
227. Akimoto M, Miyatake S, Kogishi J et al (1999) Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats. Invest Ophthalmol Vis Sci 40:273-279.
228. Uteza Y, Rouillot JS, Kobetz A et al (1999) Intravitreous transplantation of encapsulated fibroblasts secreting the human fibroblast growth factor 2 delays photoreceptor cell degeneration in Royal College of Surgeons rats. Proc Natl Acad Sci USA 96:3126-3131.
229. Neuner-Jehle M, Berghe LV, Bonnel S et al (2000) Ocular cell transfection with the human basic fibroblast growth factor gene delays photoreceptor cell degeneration in RCS rats. Hum Gene Ther 11:1875-1890.
230. Semkova I, Wolz P, Krieglstein J (1998) Neuroprotective effect of 5-HT1A receptor agonist, Bay X 3702, demonstrated in vitro and in vivo. Eur J Pharmacol 359:251-260.
231. Ahlemeyer B, Krieglstein J (1997) Stimulation of 5-HT1A receptor inhibits apoptosis induced by serum deprivation in cultured neurons from chick embryo. Brain Res 777:179-186.
232. Zhang K, Hopkins JJ, Heier JS et al (2011) Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci USA 108:6241-6245.
233. Zeiss CJ, Allore HG, Towle V, Tao W (2006) CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retina. Exp Eye Res 82:395-404.
234. Kleinman ME, Yamada K, Takeda A et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591-597.
235. Dawson DWVO, Gillis P, Crawford SE, Xu HJ, Benedict W, Bouck NP (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245-248.
236. Ohno-Matsui K, Morita I, Tombran-Tink J et al (2001) Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol 189:323-333.
237. Mori K, Gehlbach P, Yamamoto S et al (2002) AAV-mediated gene transfer of pigment epithelium- derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci 43:1994-2000.
238. Rasmussen H, Chu KW, Campochiaro P et al (2001) 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 12:2029-2032.
239. Brown DM, Kaiser PK, Michels M et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432-1444.
240. Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419-1431.
241. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ (2006) Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 113(363-372):e5.
242. Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331-335.
243. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364:1897-1908.
244. Rosenfeld PJ (2011) Bevacizumab versus ranibizumab for AMD. N Engl J Med 364:1966-1967.
245. Zhang M, Zhang J, Yan M et al (2011) A phase 1 study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration. Ophthalmology 118:672-678.
246. Kim I, Ryan AM, Rohan R et al (1999) Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 40:2115-2121.
247. Kaiser PK, Symons RC, Shah SM et al (2010) RNAi-based treatment for neovascular agerelated macular degeneration by Sirna-027. Am J Ophthalmol 150(33-39):e2.
248. Takahashi K, Saishin Y, King AG, Levin R, Campochiaro PA (2009) Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. Arch Ophthalmol 127:494-499.
249. Xie B, Shen J, Dong A, Rashid A, Stoller G, Campochiaro PA (2009) Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol 218:192-198.
250. Avraamides CJ, Garmy-Susini B, Varner JA (2008) Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8:604-617.
251. Orecchia A, Lacal PM, Schietroma C, Morea V, Zambruno G, Failla CM (2003) Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin. J Cell Sci 116:3479-3489.
252. Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591-1598.
253. Mitchell TS, Bradley J, Robinson GS, Shima DT, Ng YS (2008) RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis 11:141-151.
254. Jo N, Mailhos C, Ju M et al (2006) Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 168:2036-2053.
255. Klement G, Baruchel S, Rak J et al (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24.
256. Lee CG, Heijn M, di Tomaso E et al (2000) Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565-5570.
257. Kaiser PK, Boyer DS, Garcia R et al (2009) Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Ophthalmology 116:747-755, 755e1.
258. Augustin AJ, Puls S, Offermann I (2007) Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina 27:133-140.
259. Forte R, Bonavolonta P, Benayoun Y, Adenis JP, Robert PY (2011) Intravitreal ranibizumab and bevacizumab in combination with full-fluence verteporfin therapy and dexamethasone for exudative age-related macular degeneration. Ophthalmic Res 45:129-134.
260. Kaiser PK (2010) Combination therapy with verteporfin and anti-VEGF agents in neovascular age-related macular degeneration: where do we stand? Br J Ophthalmol 94:143-145.
261. Verteporfin In Photodynamic Therapy Study Group (2001) Verteporfin therapy of subfoveal choroidal neovascularization in age- related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization- verteporfin in photodynamic therapy report. Am J Ophthalmol 131:541-560.
262. Azab M, Boyer DS, Bressler NM et al (2005) Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol 123:448-457.
263. Schmidt-Erfurth U, Michels S, Barbazetto I, Laqua H (2002) Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci 43:830-841.
264. Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, Michels S, Beckendorf A, Naumann GO (2003) Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 44:4473-4480.
265. Lim JY, Lee SY, Kim JG, Lee JY, Chung H, Yoon YH (2010) Intravitreal bevacizumab alone versus in combination with photodynamic therapy for the treatment of neovascular maculopathy in patients aged 50 years or older: 1-year results of a prospective clinical study. Acta Ophthalmol.
266. Avila MP, Farah ME, Santos A et al (2009) Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD. Retina 29:157-169.
267. Avila MP, Farah ME, Santos A, Duprat JP, Woodward BW, Nau J (2009) Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol 93:305-309.
268. Moshfeghi DM, Kaiser PK, Gertner M (2011) Stereotactic low-voltage x-ray irradiation for age-related macular degeneration. Br J Ophthalmol 95:185-188.
269. Rosenfeld PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi B (2011) Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology 118:523-530.
270. Sun CP, Usui T, Yu F et al (2009) Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs. Integr Biol (Camb) 1:123-130.
271. Wong PK, Yu F, Shahangian A, Cheng G, Sun R, Ho CM (2008) Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm. Proc Natl Acad Sci USA 105:5105-5110.
272. Sun H, Nathans J (2001) Mechanistic studies of ABCR, the ABC transporter in photoreceptor outer segments responsible for autosomal recessive Stargardt disease. J Bioenerg Biomembr 33:523-530.
273. Donoso LA, Kim D, Frost A, Callahan A, Hageman G (2006) The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 51:137-152.