Current and investigational pharmacotherapeutic approaches for modulating retinal angiogenesis

Expert Review of Clinical Pharmacology

Volumn 7, Issue 3, 2014, Pages 375-391

  Todorich, Bozho ^a   Yiu, Glenn ^a   Hahn, Paul ^a  

^a DUKE UNIVERSITY EYE CENTER   (United States)

Author keywords

Aflibercept; Age related macular degeneration; Bevacizumab; Choroidal neovascularization; Diabetic retinopathy; Ranizbizumab; Retinal neovascularization

Indexed keywords

AFLIBERCEPT; ANGIOGENESIS INHIBITOR; ANGIOGENESIS MODULATOR; BEVACIZUMAB; BINDING PROTEIN; CELL ADHESION MOLECULE; CHIMERIC PROTEIN; COMPLEMENT FACTOR H; DESIGNED ANKYRIN REPEAT PROTEIN; DRUG CARRIER; EYLEA VEGF TRAP EYE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INTEGRIN; PEGAPTANIB; PROTEIN TYROSINE KINASE INHIBITOR; RANIBIZUMAB; SCLEROPROTEIN; TIE RECEPTOR; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN 165; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; MONOCLONAL ANTIBODY;

ANGIOGENESIS; CELL CYCLE ARREST; CELL DIFFERENTIATION; COST CONTROL; COST EFFECTIVENESS ANALYSIS; DISEASE COURSE; DNA DAMAGE; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG PENETRATION; DRUG SAFETY; DRUG TOLERABILITY; EXPERIMENTAL THERAPY; FLUORESCENCE ANGIOGRAPHY; HUMAN; HYPOXIA; IONIZING RADIATION; LIGAND BINDING; LONG TERM CARE; NONHUMAN; OPTICAL COHERENCE TOMOGRAPHY; OXYGEN DIFFUSION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PIGMENT EPITHELIUM; RADIOTHERAPY; RANDOMIZED CONTROLLED TRIAL (TOPIC); RETINA BLOOD VESSEL; RETINA DETACHMENT; RETINA MACULA AGE RELATED DEGENERATION; RETINA NEOVASCULARIZATION; RETINA VEIN OCCLUSION; RETINAL ANGIOGENESIS; REVIEW; SUBRETINAL NEOVASCULARIZATION; SYSTEMATIC REVIEW; UPREGULATION; VITREOUS BODY; ANIMAL; ANTAGONISTS AND INHIBITORS; CHOROIDAL NEOVASCULARIZATION; CLINICAL TRIAL (TOPIC); METABOLISM; PATHOLOGY; RETINAL NEOVASCULARIZATION; SIGNAL TRANSDUCTION;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTIBODIES, MONOCLONAL; CHOROIDAL NEOVASCULARIZATION; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; RETINAL NEOVASCULARIZATION; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84898907867     PISSN: 17512433     EISSN: 17512441     Source Type: Journal    
DOI: 10.1586/17512433.2014.890047     Document Type: Review

References (202)

1. Patan S. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J Neurooncol 2000;50(1-2):1-15
2. Campochiaro PA. Retinal and choroidal neovascularization. J Cell Physiol 2000; 184(3):301-10
3. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000;6(4): 389-95
4. Risau W. Mechanisms of angiogenesis. Nature 1997;386(6626):671-4
5. Gariano RF. Cellular mechanisms in retinal vascular development. Prog Retin Eye Res 2003;22(3):295-306
6. Sandercoe TM, Madigan MC, Billson FA, et al. Astrocyte proliferation during development of the human retinal vasculature. Exp Eye Res 1999;69(5):511-23
7. Dorrell MI, Friedlander M, Smith LEH. Retinal vascular development in retinal vascular disease. In: Antonia MJ, Thomas WG, Bernd K, Stephen JR, editors. Retinal vascular disease. Springer-Berlin; Berlin, Germany: 2007. p. 24-37
8. Jiang BMAB, Caldwell RB. Astrocytes modulate retinal vasculogenesis: effects on endothelial cell differentiation. Glia 1995;15:1-10
9. Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987;325:253-7
10. Stone JI, Alon T, Pe'er J, et al. Development of retinal vasculature is mediatedby hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neuroscience 1995;15:4738-47
11. Dumont DJ, Gradwohl G, Fong GH, et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 1994;8(16):1897-909
12. Puri MC, Rossant J, Alitalo K, et al. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J 1995;14(23): 5884-91
13. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380(6573): 435-9
14. Breier G, Damert A, Plate KH, RisauW. Angiogenesis in embryos and ischemic diseases. Thromb Haemost 1997;78(1):678-83
15. Hanahan D. Signaling vascular morphogenesis and maintenance. Science 1997;277(5322): 48-50
16. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277(5322):55-60
17. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxiainducible factor1. Mol Cell Biol 1996; 16(9):4604-13
18. Gerber HP, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 1997; 272(38):23659-67
19. Pierce EA, Avery RL, Foley ED, et al. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 1995;92(3): 905-9
20. Gyllensten LJ, Hellstrom BE. Experimental approach to the pathogenesis of retrolental fibroplasia. I. Changes of the eye induced by exposure of newborn mice to concentrated oxygen. Acta Paediatr Suppl 1954;43(100):131-48
21. Aguilar E, Dorrell MI, Friedlander D, et al. Chapter 6. Ocular models of angiogenesis. Methods Enzymol 2008;444:115-58
22. Gariano RF, Gardner TW. Retinal angiogenesis in development and disease. Nature 2005;438(7070):960-6
23. Madan A, Penn JS. Animal models of oxygen-induced retinopathy. Front Biosci 2003;8:d1030-43
24. Stahl A, Connor KM, Sapieha P, et al. The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 2010;51(6): 2813-26
25. Yoshida T, Zhang H, Iwase T, et al. Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular neovascularization. FASEB J 2010;24(6): 1759-67
26. Vavilala DT, O'Bryhim BE, Ponnaluri VK, et al. Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model. Biochem Biophys Res Commun 2013;438(4):697-702
27. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118(4):445-50
28. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331(22):1480-7
29. Pe'er J, Shweiki D, Itin A, et al. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest 1995;72(6): 638-45
30. Tripathi RC, Li J, Tripathi BJ, et al. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology 1998;105(2):232-7
31. Robinson GS, Pierce EA, Rook SL, et al. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA 1996;93(10):4851-6
32. Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 1996;114(1):66-71
33. Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 1996;114(8): 964-70
34. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103(11): 1820-8
35. Ozaki H, Hayashi H, Vinores SA, et al. Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 1997; 64(4):505-17.
36. Okamoto N, Tobe T, Hackett SF, et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 1997;151(1):281-91
37. Sandner P, Wolf K, Bergmaier U, et al. Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro. Kidney Int 1997;51(2):448-53
38. Punglia RS, Lu M, Hsu J, et al. Regulation of vascular endothelial growth factor expression by insulin-like growth factor I. Diabetes 1997;46(10):1619-26
39. Simo R, Carrasco E, Garcia-Ramirez M, Hernandez C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diab Rev 2006; 2(1):71-98
40. Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the macular photocoagulation study. Arch Ophthalmol 1991;109:1242-57
41. Ross RD, Barofsky JM, Cohen G, et al. Presumed macular choroidal watershed vascular filling, choroidal neovascularization, and systemic vascular disease in patients with age-related macular degeneration. Am J Ophthalmol 1998;125(1):71-80
42. Wells JA, Murthy R, Chibber R, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol 1996;80(4):363-6
43. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011; 364(20):1897-908
44. The CATT Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: 2-year results. Ophthalmology 2012;119(7):1388-98
45. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14):1419-31
46. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14): 1432-44
47. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100(10):1519-35
48. Ryan SJ. Subretinal neovascularization. Natural history of an experimental model. Arch Ophthalmol 1982;100(11): 1804-9
49. Dobi ET, Puliafito CA, Destro M. A new model of experimental choroidal neovascularization in the rat. Arch Ophthalmol 1989;107(2):264-9
50. Frank RN, Das A, Weber ML. A model of subretinal neovascularization in the pigmented rat. Curr Eye Res 1989;8(3): 239-47
51. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem 1999;74(1):135-43
52. Killingsworth MC, Sarks JP, Sarks SH. Macrophages related to Bruch's membrane in age-related macular degeneration. Eye (Lond) 1990;4(Pt 4):613-21
53. Dastgheib K, Green WR. Granulomatous reaction to Bruch's membrane in age-related macular degeneration. Arch Ophthalmol 1994;112(6):813-18
54. Sepp T, Khan JC, Thurlby DA, et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47(2):536-40
55. Maloney SC, Fernandes BF, Castiglione E, et al. Expression of cyclooxygenase-2 in choroidal neovascular membranes from age-related macular degeneration patients. Retina 2009;29(2):176-80
56. Rezaei KA, Toma HS, Cai J, et al. Reduced choroidal neovascular membrane formation in cyclooxygenase-2 null mice. Invest Ophthalmol Vis Sci 2011;52(2):701-7
57. Yanni SE, Barnett JM, Clark ML, Penn JS. The role of PGE2 receptor EP4 in pathologic ocular angiogenesis. Invest Ophthalmol Vis Sci 2009;50(11): 5479-86
58. Schoenberger SD, Kim SJ. Nonsteroidal anti-inflammatory drugs for retinal disease. Int J Inflam 2013;2013:281981
59. Russo A, Costagliola C, Delcassi L, et al. Topical nonsteroidal anti-inflammatory drugs for macular edema. Mediators Inflamm 2013;2013:476525
60. Gokce G, Sobaci G, Durukan AH, Erdurman FC. Intravitreal triamcinolone acetonide compared with bevacizumab for the treatment of patients with macular edema secondary to central retinal vein occlusion. Postgrad Med 2013;125(5): 51-8
61. Saric B, Saric VB, Motusic R, Predovic J. Is the effect of intravitreal triamcinolone acetonide on diabetic macular edema dosedependent? Eur J Ophthalmol 2014;24(2): 221-7
62. Katsura Y, Okano T, Matsuno K, et al. Erythropoietin is highly elevated in vitreous fluid of patients with proliferative diabetic retinopathy. Diabetes Care 2005;28(9): 2252-4
63. Olofsson B, Korpelainen E, Pepper MS, et al. Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells. Proc Natl Acad Sci USA 1998;95(20):11709-14
64. Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7(2):186-91
65. Barakat MR, Kaiser PK. VEGF inhibitors for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs 2009;18(5):637-46
66. Ng EW, Shima DT, Calias P, et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 2006;5(2):123-32
67. Green LS, Jellinek D, Bell C, et al. Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor. Chem Biol 1995; 2(10):683-95
68. Ruckman J, Green LS, Beeson J, et al. 2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGFinduced vascular permeability through interactions requiring the exon 7-encoded domain. J Biol Chem 1998;273(32): 20556-67
69. Ng EW, Adamis AP. Anti-VEGF aptamer (pegaptanib) therapy for ocular vascular diseases. Ann N Y Acad Sci 2006;1082:151-71
70. Gragoudas ES, Adamis AP, Cunningham ET Jr, Group VISiONCT. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351(27):2805-16
71. D'Amico DJ. VEGF inhibition study in ocular neovascularization (VISION): Second year efficacy data. (VEGF inhibition study in ocular neovascularization (VISION) clinical trial group). Invest Ophthalmol Vis Sci 2005;46:E abstract
72. Eyetech Pharmaceuticals Inc; Pfizer Inc. Pegaptanib sodium injection in the treatment of neovascular age-related macular degeneration. Briefing Document for the Dermatologic and Ophthalmic Drugs Advisory Committee. 2004
73. Friberg TR. VEGF inhibition study in ocular neovascularization (Vision): outcomes from the phase II/III macugen pivitol trials (macugen study group). Update on VISION trials, European Vitreoretinal Society. Available from: www.evrs.eu/vegfinhibition- study-in-ocularneovascularization- vision-outcomes-fromthe- phase-IIIii-macugen-pivitol-trials/ [Last] [accessed 24 January 2014]
74. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 2002; 120(3):338-46
75. Chen Y, Wiesmann C, Fuh G, et al. Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. J Mol Biol 1999;293(4):865-81
76. Rosenfeld PJ, Schwartz SD, Blumenkranz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology 2005;112(6): 1048-53
77. Magdelaine-Beuzelin C, Pinault C, Paintaud G, Watier H. Therapeutic antibodies in ophthalmology: old is new again. MAbs 2010;2(2):176-80
78. Zou L, Lai H, Zhou Q, Xiao F. Lasting controversy on ranibizumab and bevacizumab. Theranostics 2011;1: 395-402
79. Jackson TL, Antcliff RJ, Hillenkamp J, Marshall J. Human retinal molecular weight exclusion limit and estimate of species variation. Invest Ophthalmol Vis Sci 2003; 44(5):2141-6
80. Gaudreault J, Fei D, Rusit J, et al. Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 2005;46(2):726-33
81. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355(14):1419-31
82. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355(14): 1432-44
83. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145(2):239-48
84. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am J Ophthalmol 2010;150(3):315-24. e311
85. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143(4):566-83
86. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009; 148(1):43-58.e41
87. Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 2011; 118(4):663-71
88. Hospital UU. Lucentis compared to avastin study. a randomized, double blind, prospective multicenter study comparing the effect of intravitreal injection of bevacizumab (avastin)to ranibizumab (lucentis)when given to patients with exudative (wet) age-related macular degeneration. 2013. Available from: http:// clinicaltrials.gov/show/NCT01127360 [Last accessed 13 December 2013]
89. Boyer DS, Heier JS, Brown DM, et al. A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009;116(9):1731-9
90. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina 2004;24(5):676-98
91. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 2012;119(6):1175-83
92. FOCUS study group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol 2008;145:862-74
93. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112(6):1035-47
94. Arevalo JF, Fromow-Guerra J, Sanchez JG, et al. Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up. Retina 2008;28(10):1387-94
95. 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(4):331-5
96. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142(1):1-9
97. Aggio FB, Farah ME, Silva WC, Melo GB. Intravitreal bevacizumab for exudative age-related macular degeneration after multiple treatments. Graefes Arch Clin Exp Ophthalmol 2007;245(2):215-20
98. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006; 26(3):279-84
99. Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26(3):275-8
100. Hudson PJ, Souriau C. Engineered antibodies. Nat Med 2003;9(1):129-34
101. Kodjikian L, Souied EH, Mimoun G, Mauget-Fays̈se M. Ranibizumab vs. Bevacizumab for Neovascular AMD: one-year results from the GEFAL randomized trial. Ophthalmology 2013; 120(11):2300-9
102. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119(7):1399-411
103. Sawada O, Kawamura H, Kakinoki M, et al. Vascular endothelial growth factor in aqueous humor before and after intravitreal injection of bevacizumab in eyes with diabetic retinopathy. Arch Ophthalmol 2007;125(10):1363-6
104. Peters S, Heiduschka P, Julien S, et al. Immunohistochemical localisation of intravitreally injected bevacizumab in the anterior chamber angle, iris and ciliary body of the primate eye. Br J Ophthalmol 2008; 92(4):541-4
105. Wakabayashi T, Oshima Y, Sakaguchi H, et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115(9):1571-80.1580.e1571-1573
106. Saito Y, Higashide T, Takeda H, et al. Clinical factors related to recurrence of anterior segment neovascularization after treatment including intravitreal bevacizumab. Am J Ophthalmol 2010; 149(6):964-72.e961
107. Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26(3):352-4
108. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113(10): 1695.e1691-1615
109. Bakri SJ, Donaldson MJ, Link TP. Rapid regression of disc neovascularization in a patient with proliferative diabetic retinopathy following adjunctive intravitreal bevacizumab. Eye (Lond) 2006;20(12):1474-5
110. Mason JO 3rd, Nixon PA, White MF. Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142(4):685-8
111. Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina 2006;26(3):354-6
112. Chen E, Park CH. Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina 2006;26(6):699-700
113. Ishikawa K, Honda S, Tsukahara Y, Negi A . Preferable use of intravitreal bevacizumab as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy. Eye (Lond) 2009;23(1):108-11
114. da R Lucena D, Ribeiro JA, Costa RA, et al. Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study). Br J Ophthalmol 2009;93(5):688-91
115. Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 2008;92(2): 213-16
116. Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008;246(7):1061-3
117. Kychenthal A, Dorta P. Vitrectomy after intravitreal bevacizumab (Avastin) for retinal detachment in retinopathy of prematurity. Retina 2010;30(4 Suppl):S32-6
118. Lee JY, Chae JB, Yang SJ, et al. Effects of intravitreal bevacizumab and laser in retinopathy of prematurity therapy on the development of peripheral retinal vessels. Graefes Arch Clin Exp Ophthalmol 2010; 248(9):1257-62
119. Micieli JA, Surkont M, Smith AF. A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol 2009; 148(4):536-43.e532
120. Lalwani GA, Berrocal AM, Murray TG, et al. Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. Retina 2008;28(3 Suppl): S13-18
121. Mintz-Hittner HA, Kuffel RR Jr. Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina 2008;28(6):831-8
122. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364(7):603-15
123. Saint-Geniez M, Maharaj AS, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on muller cells and photoreceptors. PLoS One 2008;3(11):e3554
124. Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 1999;846(2): 219-28
125. Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 1999;19(14):5731-40
126. Blaauwgeers HG, Holtkamp GM, Rutten H, et al. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 1999;155(2): 421-8
127. Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer 2004;4: S81-5
128. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3(5):391-400
129. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012;15(2): 171-85
130. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119(12): 2537-48
131. Regeneron Pharmaceuticals Inc. Two year results of phase 3 studies with EYLEATM (aflibercept) injection in wet AMD show sustained improvement in visual acuity [press release]. Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA. Available from: http://investor.regeneron.com/releasedetail. cfm?releaseid=629800 [Last accessed 5 December 2011]
132. Regeneron Pharmaceuticals Inc. Bayer and regeneron report positive top-line results of two phase-3 studies with VEGF trap-eye in wet age-related macular degeneration (press release). Regeneron Pharmaceuticals, Inc. Tarrytown, NY, USA. Available from: http://newsroom.regeneron.com/releasedetail. cfm?releaseid=532099 [Last accessed 22 November 2010]
133. Stewart MW. Clinical and differential utility of VEGF inhibitors in wet age-related macular degeneration: focus on aflibercept. Clin Ophthalmol 2012;6:1175-86
134. Bakall B, Folk JC, Boldt HC, et al. Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 2013;156(1):15-22.e11
135. The Diabetic Retinopathy Study Research Group. Indications for photocoagulation treatment of diabetic retinopathy: diabetic Retinopathy Study Report no. 14. Int Ophthalmol Clin 1987;27:239-53
136. Krypton laser photocoagulation for idiopathic neovascular lesions. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1990;108(6):832-7
137. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1991; 109(9):1220-31
138. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Macular Photocoagulation Study Group. Arch Ophthalmol 1991;109(8):1109-14
139. Kaiser PK, Boyer DS, Cruess AF, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology 2012; 119(5):1001-10
140. Larsen M, Schmidt-Erfurth U, Lanzetta P, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results. Ophthalmology 2012;119(5):992-1000
141. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials - TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol 1999;117(10):1329-45
142. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial-VIP report no. 1. Ophthalmology 2001;108(5):841-52
143. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 2012;32(8):1453-64
144. Awh CC, Erickson SR, De Juan E Jr. Phase 1 two-year device safety and explantation experience with an intravitreal ranibizumab sustained delivery implant. American Academy of Ophthalmology Annual Meeting; 16 - 19 November 2013; New Orleans, LA, USA
145. Lukason M, DuFresne E, Rubin H, et al. Inhibition of choroidal neovascularization in a nonhuman primate model by intravitreal administration of an AAV2 vector expressing a novel anti-VEGF molecule. Mol Ther 2011;19(2):260-5
146. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med 2008;358(21):2240-8
147. Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther 2009;20(9): 999-1004
148. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 2008;19(10):979-90
149. Pechan P, Rubin H, Lukason M, et al. Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization. Gene Ther 2009; 16(1):10-16
150. Stahl A, Stumpp MT, Schlegel A, et al. Highly potent VEGF-A-antagonistic DARPins as anti-angiogenic agents for topical and intravitreal applications. Angiogenesis 2013;16(1):101-11
151. Binz HK, Amstutz P, Kohl A, et al. High-affinity binders selected from designed ankyrin repeat protein libraries. Nat Biotechnol 2004;22(5):575-82
152. Binz HK, Stumpp MT, Forrer P, et al. Designing repeat proteins: well-expressed, soluble and stable proteins from combinatorial libraries of consensus ankyrin repeat proteins. J Mol Biol 2003;332(2): 489-503
153. ClinicalTrials.gov. NCT01086761. Study of MP0112 intravitreal injection in patients with wet age related macular degeneration. Available from: www.clinicaltrials.gov/show/ NCT01086761 [Last accessed 7 December 2013]
154. Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol 2013;155(4):697-704. 704 e691-692
155. Krishnan L, Krishnan EC, Jewell WR. Immediate effect of irradiation on microvasculature. Int J Radiat Oncol Biol Phys 1988;15(1):147-50
156. Chakravarthy U, Gardiner TA, Archer DB, Maguire CJ. A light microscopic and autoradiographic study of non-irradiated and irradiated ocular wounds. Curr Eye Res 1989;8(4):337-48
157. Myers AL, Williams RF, Ng CY, et al. Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. J Pediatr Surg 2010;45(6):1080-5
158. Willett CG, Duda DG, Czito BG, et al. Targeted therapy in rectal cancer. Oncology 2007;21(9):1055-65.discussion 1065, 1070, 1075 passim
159. Duda DG, Batchelor TT, Willett CG, Jain RK. VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med 2007; 13(6):223-30
160. Willett CG, Kozin SV, Duda DG, et al. Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice. Semin Oncol 2006;33(5 Suppl 10):S35-40
161. Nieder C, Wiedenmann N, Andratschke N, Molls M. Current status of angiogenesis inhibitors combined with radiation therapy. Cancer Treat Rev 2006;32(5): 348-64
162. Jackson TL, Dugel PU, Bebchuk JD, et al. Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography. Ophthalmology 2013;120(8):1597-603
163. Dugel PU, Bebchuk JD, Nau J, et al. Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology 2013; 120(2):317-27
164. Dugel PU, Petrarca R, Bennett M, et al. Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety and efficacy results. Ophthalmology 2012; 119(7):1425-31
165. Rahimi N. VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy. Front Biosci 2006;11: 818-29
166. Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs 2008;17(2):253-61
167. GlaxoSmithKline. Safety study to evaluate pazopanib eye drops in healthy volunteers; 2013. Available from: http://clinicaltrials. gov/show/NCT01072214
168. McLaughlin MM, Paglione MG, Slakter J, et al. Initial exploration of oral pazopanib in healthy participants and patients with age-related macular degeneration. JAMA Ophthalmol 2013;131(12):1595-601
169. Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol
170. Novartis NCI. Safety and efficacy of oral PTK787 in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD) (ADVANCE). 2013. Available from: http:// clinicaltrials.gov/ show/NCT00138632
171. Luna J, Tobe T, Mousa SA, et al. Antagonists of integrin alpha v beta 3 inhibit retinal neovascularization in a murine model. Lab Invest 1996.75(4): 563-73
172. David B, Campochiaro PA, Heier JS, et al. Integrin peptide therapy: the first human wet AMD experience. American Academy of Ophthalmology Annual Meeting; New Orleans, LA, USA; 2013
173. Hall AP. Review of the pericyte during angiogenesis and its role in cancer and diabetic retinopathy. Toxicol Pathol 2006; 34(6):763-75
174. Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111(9):1287-95
175. 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(9):1591-8
176. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004;18(2):338-40
177. Boyer DS OA-PiASG. Combined inhibition of platelet derived (PDGF) and vascular endothelial (VEGF) growth factors for the treatment of neovascular age-related macular degeneration (NV-AMD) - results of a phase 1 study. Invest Ophthalmol Vis Sci 2009;50:1260
178. Jumper JM. ASRS Preferences and Trends (PAT) Survey. 2012. Available from: www. asrs.org/annual-meeting/2012-daily-updatesunday [Last accessed 5 December 2013]
179. Goldberg RA, Flynn HW Jr, Isom RF, et al. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol 2012; 153(2):204-8.e201
180. Gonzalez S, Rosenfeld PJ, Stewart MW, et al. Avastin doesn't blind people, people blind people. Am J Ophthalmol 2012; 153(2):196-203.e191
181. Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115(12):2199-205
182. Keane PA, Liakopoulos S, Ongchin SC, et al. Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49(7):3115-20
183. Reduced fluence visudyne-anti-VEGFdexamethasone in combination for amd lesions (RADICAL) Clinical Trials.gov. 2014. Available from: http://clinicaltrials. gov/ct2/show/NCT00492284 [Last accessed 24 January 2015]
184. Aging. USSSCo. Statement of Jonathan Blum, Deputy Administrator and Director, Center for Medicare and Medicaid Services, on sustaining the Medicare program through lower costs, before the United States Senate Special Committee on Aging. Available from: http://aging.senate.gov/events/hr236jb. pdf [Last accessed 21 July 2011]
185. Kaufman SC, Ferris FL 3rd, Seigel DG, et al. Factors associated with visual outcome after photocoagulation for diabetic retinopathy. Diabetic Retinopathy Study Report #13. Invest Ophthalmol Vis Sci 1989;30(1):23-8
186. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol 1997;115(4):486-91
187. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol 1986;104(1):34-41
188. Rudkin AK, Lee AW, Chen CS. Ocular neovascularization following central retinal artery occlusion: prevalence and timing of onset. Eur J Ophthalmol 2010;20(6): 1042-6
189. Hayreh SS, Podhajsky P. Ocular neovascularization with retinal vascular occlusion. II. Occurrence in central and branch retinal artery occlusion. Arch Ophthalmol 1982;100(10):1585-96
190. Terelak-Borys B, Skonieczna K, Grabska-Liberek I. Ocular ischemic syndrome - a systematic review. Med Sci Monit 2012;18(8):RA138-44
191. Ansem RP, Bastiaensen LA. Glaucoma following retinal detachment operations. Doc Ophthalmol 1987;67(1-2): 19-24
192. Goldberg MF. Retinal neovascularization in sickle cell retinopathy. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol 1977;83(3 Pt 1): OP409-31
193. Lee J, Logani S, Lakosha H, et al. Preretinal neovascularisation associated with choroidal melanoma. Br J Ophthalmol 2001;85(11): 1309-12
194. Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res 2004; 14(Suppl A):S140-4
195. Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy - clinical, histopathological, ultrastructural and experimental correlations. Eye (Lond) 1991; 5(Pt 2):239-251
196. Neelam K, Cheung CM, Ohno-Matsui K, et al. Choroidal neovascularization in pathological myopia. Prog Retin Eye Res 2012;31(5):495-525
197. Ciulla TA, Piper HC, Xiao M, Wheat LJ. Presumed ocular histoplasmosis syndrome: update on epidemiology, pathogenesis, and photodynamic, antiangiogenic, and surgical therapies. Curr Opin Ophthalmol 2001; 12(6):442-9
198. Nakagawa S, Yamashiro K, Tsujikawa A, et al. The time course changes of choroidal neovascularization in angioid streaks. Retina 2013;33(4):825-33
199. Spaide RF, Freund KB, Slakter J, et al. Treatment of subfoveal choroidal neovascularization associated with multifocal choroiditis and panuveitis with photodynamic therapy. Retina 2002;22(5):545-9
200. Mimoun G, Caillaux V, Querques G, et al. Ranibizumab for choroidal neovascularization associated with adult-onset foveomacular vitelliform dystrophy: one-year results. Retina 2013; 33(3):513-21
201. Delyfer MN, Rougier MB, Fourmaux E, et al. Laser photocoagulation for choroidal neovascular membrane associated with optic disc drusen. Acta Ophthalmol Scand 2004; 82(2):236-8
202. Spaide RF, Martin ML, Slakter J, et al. Treatment of idiopathic subfoveal choroidal neovascular lesions using photodynamic therapy with verteporfin. Am J Ophthalmol 2002;134(1):62-8