Pathway-based therapies for age-related macular degeneration: An integrated survey of emerging treatment alternatives

Retina

Volumn 30, Issue 9, 2010, Pages 1350-1367

  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

age related macular degeneration; angiogenesis; choroidal neovascularization; complement; geographic atrophy; neuroprotection; oxidative damage; treatment

Indexed keywords

ACU 4429; ACUTANE; AL 8309B; ANTI PROPERDIN AB; ARC 1905; BCX 1470; BEVACIZUMAB; C1 INH; CORTICOSTEROID; DOCOSAHEXAENOIC ACID; ECULIZUMAB; EVEROLIMUS; EYE DROPS; FENRETINIDE; GLATIRAMER; ICOSAPENTAENOIC ACID; ILUVIEN; ISOTRETINOIN; JPE 1375; LIPOFUSCIN; NEUTRAZIMAB; OT 551; PALOMID 529; PAZOPANIB; PLACEBO; PMX 025; POLYIMIDE; POT 4; PROTEIN INHIBITOR; RANIBIZUMAB; RAPAMYCIN; RECOMBINANT HUMAN CFH PROTEIN; RECOMBINANT PROTEIN; TA 106; TT 30; UNCLASSIFIED DRUG; UNINDEXED DRUG; XANTHOPHYLL; ZEAXANTHIN;

BREAST CANCER; CELL ACTIVATION; CELL MIGRATION; CHRONIC INFLAMMATION; CLINICAL TRIAL; DRUG MECHANISM; ENDOTHELIUM CELL; HEALTH SURVEY; HUMAN; MONOTHERAPY; NONHUMAN; OXIDATIVE STRESS; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PATHOGENESIS; RETINA MACULA AGE RELATED DEGENERATION; REVIEW; SUBRETINAL NEOVASCULARIZATION;

CHOROIDAL NEOVASCULARIZATION; COMPLEMENTARY THERAPIES; DRUG DISCOVERY; HUMANS; MACULAR DEGENERATION; METABOLIC NETWORKS AND PATHWAYS;

EID: 77958524704     PISSN: 0275004X     EISSN: None     Source Type: Journal    
DOI: 10.1097/IAE.0b013e3181f57e30     Document Type: Review

References (165)

1. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004;122: 598-614. (Pubitemid 38456297)
2. Donoso LA, Kim D, Frost A, Callahan A, Hageman G. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2006;51:137-152. (Pubitemid 43269939)
3. Shen JK, Dong A, Hackett SF, Bell WR, Green WR, Campochiaro PA. Oxidative damage in age-related macular degeneration. Histol Histopathol 2007;22:1301-1308. (Pubitemid 47470323)
4. Frank RN, Amin RH, Puklin JE. Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration. Am J Ophthalmol 1999; 127:694-709.
5. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A 2002;99:14682-14687. (Pubitemid 35334544)
6. Ishibashi T, Murata T, Hangai M, et al. Advanced glycation end products in age-related macular degeneration. Arch Ophthalmol 1998;116:1629-1632. (Pubitemid 29001961)
7. Hammes HP, Hoerauf H, Alt A, et al. N(epsilon)(carbox-ymethyl)lysin and the AGE receptor RAGE colocalize in age-related macular degeneration. Invest Ophthalmol Vis Sci 1999;40:1855-1859. (Pubitemid 29297167)
8. He X, Hahn P, Iacovelli J, et al. Iron homeostasis and toxicity in retinal degeneration. Prog Retin Eye Res 2007;26:649-673. (Pubitemid 47615564)
9. Hahn P, Milam AH, Dunaief JL. Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch's membrane. Arch Ophthalmol 2003;121:1099-1105. (Pubitemid 36962162)
10. Klein ML, Francis PJ, Rosner B, et al. CFH and LOC387715/ ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 2008; 115:1019-1025.
11. Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 2001;42:1051-1056. (Pubitemid 32289803)
12. Kennedy CJ, Rakoczy PE, Constable IJ. Lipofuscin of the retinal pigment epithelium: A review. Eye 1995;9:763-771. (Pubitemid 26018204)
13. Lamb TD, Pugh EN Jr. Dark adaptation and the retinoid cycle of vision. Prog Retin Eye Res 2004;23:307-380.
14. Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. 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. (Pubitemid 29331192)
15. Beharry S, Zhong M, Molday RS. N-retinylidene-phospha-tidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR). J Biol Chem 2004;279:53972-53979. (Pubitemid 40053128)
16. 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. (Pubitemid 30212743)
17. 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. (Pubitemid 46042073)
18. Imanishi Y, Batten ML, Piston DW, Baehr W, Palczewski K. Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J Cell Biol 2004;164:373-383. (Pubitemid 38174765)
19. 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. (Pubitemid 39097163)
20. Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci U S A 2005;102:13658-13663. (Pubitemid 41420904)
21. Jin M, Li S, Moghrabi WN, Sun H, Travis GH. Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 2005;122:449-459. (Pubitemid 41127145)
22. Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci U S A 2005;102:12413-12418. (Pubitemid 41266373)
23. 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: 32456-32465. (Pubitemid 37384682)
24. Farjo KM, Moiseyev G, Takahashi Y, Crouch RK, Ma JX. The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins. Invest Ophthalmol Vis Sci 2009;50:5089-5097.
25. Sparrow JR, Fishkin N, Zhou J, et al. A2E, a byproduct of the visual cycle. Vision Res 2003;43:2983-2990. (Pubitemid 37377610)
26. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411-431.
27. 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: 7227-7232.
28. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 2001;73:887-896.
29. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 2000;14:835-846.
30. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. 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 2001; 20:705-732.
31. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovasculariza-tion. Proc Natl Acad Sci U S A 2006;103:2328-2333. (Pubitemid 43271669)
32. Blom AM, Kask L, Ramesh B, Hillarp A. Effects of zinc on factor I cofactor activity of C4b-binding protein and factor H. Arch Biochem Biophys 2003;418:108-118. (Pubitemid 37159377)
33. Sivaprasad S, Adewoyin T, Bailey TA, et al. Estimation of systemic complement C3 activity in age-related macular degeneration. Arch Ophthalmol 2007;125:515-519. (Pubitemid 46596724)
34. Amara U, Rittirsch D, Flierl M, et al. Interaction between the coagulation and complement system. Adv Exp Med Biol 2008;632:71-79.
35. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-389. (Pubitemid 40530070)
36. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421-424. (Pubitemid 40530082)
37. 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. (Pubitemid 40530081)
38. Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U. 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. (Pubitemid 44470363)
39. 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. (Pubitemid 46678196)
40. 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. (Pubitemid 43200637)
41. 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. (Pubitemid 44325931)
42. 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.
43. 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. (Pubitemid 47354881)
44. 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. (Pubitemid 47236280)
45. 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.
46. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007;39:1200-1201. (Pubitemid 47482689)
47. Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM. Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 2009;17: 100-104.
48. Thurman JM, Holers VM. The central role of the alternative complement pathway in human disease. J Immunol 2006;176: 1305-1310.
49. Sohn JH, Kaplan HJ, Suk HJ, Bora PS, Bora NS. Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest Ophthal-mol Vis Sci 2000;41:3492-3502.
50. 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.
51. Wu Z, Lauer TW, Sick A, Hackett SF, Campochiaro PA. Oxidative stress modulates complement factor H expression in retinal pigmented epithelial cells by acetylation of FOXO3. J Biol Chem 2007;282:22414-22425. (Pubitemid 47267308)
52. Zhou J, Jang YP, Kim SR, Sparrow JR. Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium. Proc Natl Acad Sci U S A 2006;103:16182-16187. (Pubitemid 44715171)
53. Hollyfield JG, Bonilha VL, Rayborn ME, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 2008;14:194-198. (Pubitemid 351214555)
54. Dewan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989-992. (Pubitemid 44749943)
55. Rivera A, Fisher SA, Fritsche LG, et al. 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 2005; 14:3227-3236. (Pubitemid 41631297)
56. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005;77:389-407. (Pubitemid 41192646)
57. Schmidt S, Hauser MA, Scott WK, et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 2006;78: 852-864.
58. Kanda A, Chen W, Othman M, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A 2007;104:16227-16232. (Pubitemid 350099389)
59. Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, Sue CM. Mitochondrial DNA haplogroups and age-related maculopathy. Arch Ophthalmol 2007;125:1235-1240. (Pubitemid 47403031)
60. A randomized, placebo-controlled, clinical trial of highdose 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. (Pubitemid 32963246)
61. 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. (Pubitemid 44264531)
62. Formelli F, Clerici M, Campa T, et al. Five-year administration of fenretinide: pharmacokinetics and effects on plasma retinol concentrations. J Clin Oncol 1993;11:2036-2042. (Pubitemid 23304631)
63. Formelli F, Carsana R, Costa A, et al. Plasma retinol level reduction by the synthetic retinoid fenretinide: A one year follow-up study of breast cancer patients. Cancer Res 1989; 49:6149-6152. (Pubitemid 19274183)
64. Decensi A, Fontana V, Fioretto M, et al. Long-term effects of fenretinide on retinal function. Eur J Cancer 1997;33: 80-84. (Pubitemid 27099572)
65. Conley B, O'Shaughnessy J, Prindiville S, et al. 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 2000; 18:275-283. (Pubitemid 30056415)
66. Costa A, Malone W, Perloff M, et al. Tolerability of the synthetic retinoid Fenretinide (HPR). Eur J Cancer Clin Oncol 1989;25:805-808. (Pubitemid 19164323)
67. Camerini T, Mariani L, De Palo G, et al. Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 2001;19:1664-1670. (Pubitemid 32230866)
68. Garaventa A, Luksch R, Lo Piccolo MS, et al. Phase I trial and pharmacokinetics of fenretinide in children with neuroblas-toma. Clin Cancer Res 2003;9:2032-2039. (Pubitemid 36687622)
69. Decensi A, Torrisi R, Bruno S, et al. Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate end point. Cancer Epidemiol Biomarkers Prev 2000;9:1071-1078.
70. Follen M, Atkinson EN, Schottenfeld D, et al. A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix. Clin Cancer Res 2001;7:3356-3365. (Pubitemid 33069966)
71. Puduvalli VK, Yung WK, Hess KR, et al. Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol 2004;22:4282-4289. (Pubitemid 41185149)
72. Mariani L, Formelli F, De Palo G, et al. Chemoprevention of breast cancer with fenretinide (4-HPR): study of long-term visual and ophthalmologic tolerability. Tumori 1996;82: 444-449. (Pubitemid 27013325)
73. Kaiser-Kupfer MI, Peck GL, Caruso RC, Jaffe MJ, DiGiovanna JJ, Gross EG. Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Ophthalmol 1986;104:69-70. (Pubitemid 16172230)
74. Decensi A, Torrisi R, Polizzi A, et al. Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. J Natl Cancer Inst 1994;86:105-110. (Pubitemid 24040147)
75. Torrisi R, Parodi S, Fontana V, et al. Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients. Cancer Epidemiol Biomarkers Prev 1994;3:507-510. (Pubitemid 24280975)
76. Caruso RC, Zujewski J, Iwata F, et al. Effects of fenretinide (4-HPR) on dark adaptation. Arch Ophthalmol 1998;116: 759-763. (Pubitemid 28292729)
77. Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci U S A 2003;100: 4742-4747. (Pubitemid 36457800)
78. 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 U S A 2001;98: 1835-1840. (Pubitemid 32165584)
79. Burton GW, Ingold KU. Beta-carotene: an unusual type of lipid antioxidant. Science 1984;224:569-573.
80. Russell RM. The enigma of beta-carotene in carcinogenesis: what can be learned from animal studies. J Nutr 2004;134: 262S-268S. (Pubitemid 38057460)
81. Zarbin M. Should corticosteroids be considered as part of the standard care with photodynamic therapy? Arch Ophthalmol 2006;124:563-571.
82. 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. (Pubitemid 43119497)
83. Giese MJ, Mondino BJ, Glasgow BJ, et al. Complement system and host defense against staphylococcal endophthal-mitis. Invest Ophthalmol Vis Sci 1994;35:1026-1032.
84. Aizuss DH, Mondino BJ, Sumner HL, Dethlefs BA. The complement system and host defense against Pseudomonas endophthalmitis. Invest Ophthalmol Vis Sci 1985;26:1262-1266. (Pubitemid 15237917)
85. Yang Z, Stratton C, Francis PJ, et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 2008;359. doi:10.1056/NEJMoa0802437.
86. Schmid-Kubista KE, Tosakulwong N, Wu Y, et al. Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50: 5070-5079.
87. Landa G, Butovsky O, Shoshani J, Schwartz M, Pollack A. Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related macular degeneration. Curr Eye Res 2008;33:1011-1013.
88. Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial. Ophthalmology 2006;113:1974-1986.
89. Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, Anderson DH. 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 2002;99:11830-11835.
90. Isas JM, Luibl V, Johnson LV, et al. Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci 2010;51:1304-1310.
91. Chaum E. Retinal neuroprotection by growth factors: A mechanistic perspective. J Cell Biochem 2003;88: 57-75. (Pubitemid 36015075)
92. Wenzel A, Grimm C, Samardzija M, Reme CE. Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res 2005;24:275-306. (Pubitemid 40021788)
93. LaVail MM, Unoki K, Yasumura D, Matthes MT, Yanco-poulos GD, Steinberg RH. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci U S A 1992;89: 11249-11253.
94. LaVail MM, Yasumura D, Matthes MT, et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 1998;39:592-602. (Pubitemid 28110693)
95. Cao W, Tombran-Tink J, Elias R, Sezate S, Mrazek D, McGinnis JF. In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2001;42:1646-1652. (Pubitemid 32520760)
96. Cayouette M, Smith SB, Becerra SP, Gravel C. Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis 1999;6:523-532. (Pubitemid 30036622)
97. Miyazaki M, Ikeda Y, Yonemitsu Y, et al. 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 2003;10: 1503-1511. (Pubitemid 36987144)
98. Schweigerer L, Malerstein B, Neufeld G, Gospodarowicz D. Basic fibroblast growth factor is synthesized in cultured retinal pigment epithelial cells. Biochem Biophys Res Commun 1987;143:934-940. (Pubitemid 17048360)
99. Waldbillig RJ, Pfeffer BA, Schoen TJ, et al. Evidence for an insulin-like growth factor autocrine-paracrine system in the retinal photoreceptor-pigment epithelial cell complex. J Neurochem 1991;57:1522-1533.
100. Takagi H, Yoshimura N, Tanihara H, Honda Y. Insulin-like growth factor-related genes, receptors, and binding proteins in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 1994;35:916-923. (Pubitemid 24079822)
101. Tombran-Tink J, Barnstable CJ. PEDF: A multifaceted neurotrophic factor. Nat Rev Neurosci 2003;4:628-636. (Pubitemid 37280158)
102. Wen R, Cheng T, Song Y, et al. Continuous exposure to bright light upregulates bFGF and CNTF expression in the rat retina. Curr Eye Res 1998;17:494-500. (Pubitemid 28306504)
103. Campochiaro PA, Chang M, Ohsato M, et al. Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor. J Neurosci 1996;16:1679-1688. (Pubitemid 26145945)
104. Cayouette M, Gravel C. Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum Gene Ther 1997;8:423-430. (Pubitemid 27140545)
105. Leveillard T, Mohand-Said S, Lorentz O, et al. Identification and characterization of rod-derived cone viability factor. Nat Genet 2004;36:755-759. (Pubitemid 38886639)
106. Chalmel F, Leveillard T, Jaillard C, et al. Rod-derived Cone Viability Factor-2 is a novel bifunctional-thioredoxin-like protein with therapeutic potential. BMC Mol Biol 2007; 8:74. (Pubitemid 350066525)
107. Machida S, Chaudhry P, Shinohara T, et al. Lens epithelium-derived growth factor promotes photoreceptor survival in light-damaged and RCS rats. Invest Ophthalmol Vis Sci 2001; 42:1087-1095. (Pubitemid 32289808)
108. Raz-Prag D, Zeng Y, Sieving PA, Bush RA. Photoreceptor protection by adeno-associated virus-mediated LEDGF expression in the RCS rat model of retinal degeneration: probing the mechanism. Invest Ophthalmol Vis Sci 2009;50:3897-3906.
109. Li Y, Roth S, Laser M, Ma JX, Crosson CE. Retinal preconditioning and the induction of heat-shock protein 27. Invest Ophthalmol Vis Sci 2003;44:1299-1304. (Pubitemid 36297853)
110. Yu Q, Kent CR, Tytell M. Retinal uptake of intravitreally injected Hsc/Hsp70 and its effect on susceptibility to light damage. Mol Vis 2001;7:48-56. (Pubitemid 36153651)
111. Wen R, Cheng T, Li Y, Cao W, Steinberg RH. Alpha 2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage. J Neurosci 1996;16:5986-5992. (Pubitemid 26313974)
112. 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. (Pubitemid 34948372)
113. Beltran WA, Allore HG, Johnson E, et al. CREB1/ATF1 activation in photoreceptor degeneration and protection. Invest Ophthalmol Vis Sci 2009;50:5355-5363.
114. Wahlin KJ, Campochiaro PA, Zack DJ, Adler R. 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 2000;41:927-936. (Pubitemid 30158910)
115. Azadi S, Johnson LE, Paquet-Durand F, et al. CNTF + BDNF treatment and neuroprotective pathways in the rd1 mouse retina. Brain Res 2007;1129:116-129. (Pubitemid 46048765)
116. Wahlin KJ, Adler R, Zack DJ, Campochiaro PA. Neurotrophic signaling in normal and degenerating rodent retinas. Exp Eye Res 2001;73:693-701. (Pubitemid 34014397)
117. Beltran WA, Rohrer H, Aguirre GD. Immunolocalization of ciliary neurotrophic factor receptor alpha (CNTFRalpha) in mammalian photoreceptor cells. Mol Vis 2005;11:232-244. (Pubitemid 41358287)
118. Gao H, Hollyfield JG. Basic fibroblast growth factor: increased gene expression in inherited and light-induced photoreceptor degeneration. Exp Eye Res 1996;62:181-189. (Pubitemid 26141514)
119. Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM. Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat. J Neurosci 1992;12:3554-3567.
120. Wen R, Song Y, Cheng T, et al. Injury-induced upregulation of bFGF and CNTF mRNAS in the rat retina. J Neurosci 1995;15:7377-7385.
121. Goureau O, Jeanny JC, Becquet F, Hartmann MP, Courtois Y. Protection against light-induced retinal degeneration by an inhibitor of NO synthase. Neuroreport 1993;5:233-236. (Pubitemid 24026241)
122. Kaldi I, Dittmar M, Pierce P, Anderson RE. L-NAME protects against acute light damage in albino rats, but not against retinal degeneration in P23H and S334ter transgenic rats. Exp Eye Res 2003;76:453-461. (Pubitemid 36299057)
123. Grimm C, Wenzel A, Stanescu D, et al. Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration. J Neurosci 2004;24:5651-5658. (Pubitemid 38857219)
124. Maeda A, Golczak M, Maeda T, Palczewski K. Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina. Invest Ophthalmol Vis Sci 2009;50: 5435-5443.
125. Maeda A, Maeda T, Golczak M, et al. Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J Biol Chem 2009;284:15173-15183.
126. Allikmets R. Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet 2000; 67:487-491.
127. Allikmets R, Shroyer NF, Singh N, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997;277:1805-1807. (Pubitemid 27449189)
128. Stone EM, Webster AR, Vandenburgh K, et al. Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration. Nat Genet 1998;20: 328-329. (Pubitemid 28541627)
129. Joseph RM, Li T. Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration. Invest Ophthalmol Vis Sci 1996;37:2434-2446. (Pubitemid 26391281)
130. Nir I, Kedzierski W, Chen J, Travis GH. Expression of Bcl-2 protects against photoreceptor degeneration in retinal degeneration slow (rds) mice. J Neurosci 2000;20:2150-2154. (Pubitemid 30230067)
131. Ranchon I, LaVail MM, Kotake Y, Anderson RE. Free radical trap phenyl-N-tert-butylnitrone protects against light damage but does not rescue P23H and S334ter rhodopsin transgenic rats from inherited retinal degeneration. J Neurosci 2003;23: 6050-6057. (Pubitemid 36859443)
132. Organisciak DT, Darrow RM, Barsalou L, Kutty RK, Wiggert B. Susceptibility to retinal light damage in transgenic rats with rhodopsin mutations. Invest Ophthalmol Vis Sci 2003; 44:486-492. (Pubitemid 36159688)
133. Lavail MM, Yasamura D, Matthes MT, Lau-villacorta C, Unoki K, Sung C-H, Steinberg RH. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 1998;39:592-602. (Pubitemid 28110693)
134. Akimoto M, Miyatake S, Kogishi J, et al. Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats. Invest Ophthalmol Vis Sci 1999;40: 273-279. (Pubitemid 29063822)
135. Uteza Y, Rouillot JS, Kobetz A, et al. 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 U S A 1999;96:3126-3131. (Pubitemid 29148855)
136. Neuner-Jehle M, Berghe LV, Bonnel S, et al. Ocular cell transfection with the human basic fibroblast growth factor gene delays photoreceptor cell degeneration in RCS rats. Hum Gene Ther 2000;11:1875-1890.
137. Semkova I, Wolz P, Krieglstein J. Neuroprotective effect of 5-HT1A receptor agonist, Bay X 3702, demonstrated in vitro and in vivo. Eur J Pharmacol 1998;359:251-260. (Pubitemid 28513022)
138. Ahlemeyer B, Krieglstein J. Stimulation of 5-HT1A receptor inhibits apoptosis induced by serum deprivation in cultured neurons from chick embryo. Brain Res 1997;777:179-186. (Pubitemid 28015746)
139. Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci U S A 2006;103:3896-3901. (Pubitemid 43376652)
140. Zeiss CJ, Allore HG, Towle V, Tao W. CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retina. Exp Eye Res 2006;82:395-404. (Pubitemid 43138953)
141. Kleinman ME, Yamada K, Takeda A, et al. Sequence-and target-independent angiogenesis suppression by siRNA via TLR3. Nature 2008;452:591-597. (Pubitemid 351483358)
142. Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. Science 1999;285:245-248. (Pubitemid 29329995)
143. Ohno-Matsui K, Morita I, Tombran-Tink J, et al. Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol 2001;189:323-333. (Pubitemid 33063300)
144. Mori K, Gehlbach P, Yamamoto S, et al. AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci 2002;43:1994-2000. (Pubitemid 34587052)
145. 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 neo-vascular age-related macular degeneration (AMD). Hum Gene Ther 2001;12:2029-2032.
146. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-1444. (Pubitemid 44511558)
147. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431. (Pubitemid 44511557)
148. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363.e5-372.e5.
149. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331-335. (Pubitemid 41073112)
150. Nguyen QD, Shah SM, Hafiz G, et al. A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006;113: 1522.e1-1522.e14. (Pubitemid 44292331)
151. Kim I, Ryan AM, Rohan R, et al. Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999;40:2115-2121. (Pubitemid 29365177)
152. Takahashi K, Saishin Y, King AG, Levin R, Campochiaro PA. Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. Arch Ophthalmol 2009;127:494-499.
153. Xie B, Shen J, Dong A, Rashid A, Stoller G, Campochiaro PA. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol 2009;218:192-198.
154. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 2008; 8:604-617.
155. Orecchia A, Lacal PM, Schietroma C, Morea V, Zambruno G, Failla CM. 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 2003;116: 3479-3489. (Pubitemid 37063392)
156. Benjamin LE, Hemo I, Keshet E. 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 1998;125:1591-1598. (Pubitemid 28256727)
157. Mitchell TS, Bradley J, Robinson GS, Shima DT, Ng YS. RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis 2008;11: 141-151.
158. Jo N, Mailhos C, Ju M, et al. 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 2006;168: 2036-2053. (Pubitemid 43825322)
159. Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15-R24. (Pubitemid 30217701)
160. Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:5565-5570.
161. Kaiser PK, Boyer DS, Garcia R, et al. Verteporfin photodynamic therapy combined with intravitreal bevacizu-mab for neovascular age-related macular degeneration. Ophthalmology 2009;116:747 e1-755 e1.
162. Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexameth-asone. Retina 2007;27:133-140. (Pubitemid 46245638)
163. Avila MP, Farah ME, Santos A, et al. 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 2009;29:157-169.
164. Sun CP, Usui T, Yu F, et al. Integrative systems control approach for reactivating Kaposi's sarcoma-associated herpesvirus (KSHV) with combinatory drugs. Integr Biol (Camb) 2009;1:123-130.
165. Wong PK, Yu F, Shahangian A, Cheng G, Sun R, Ho CM. Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm. Proc Natl Acad Sci U S A 2008;105:5105-5110 (Pubitemid 351738517)