Targeting VEGF in eye neovascularization: What's new?: A comprehensive review on current therapies and oligonucleotide-based interventions under development

Pharmacological Research

Volumn 103, Issue , 2016, Pages 253-269

  Amadio, Marialaura ^a   Govoni, Stefano ^a   Pascale, Alessia ^a  

^a UNIVERSITY OF PAVIA   (Italy)

Author keywords

AMD; Bevacizumab; Neovascular; Pegaptanib; Ranibizumab; VEGF Ocular angiogenesis

Indexed keywords

AFLIBERCEPT; APTAMER; AVACINCAPTAD PEGOL; BEVACIZUMAB; BEVASIRANIB; NEUROPILIN 1; OLIGONUCLEOTIDE; PEGAPTANIB; PEGPLERANIB; PF 04523655; PLATELET DERIVED GROWTH FACTOR; RANIBIZUMAB; SIRNA 027; SMALL INTERFERING RNA; UNCLASSIFIED DRUG; VASCULOTROPIN; VASCULOTROPIN 165; VASCULOTROPIN RECEPTOR 2; ANGIOGENESIS INHIBITOR; VASCULOTROPIN A;

AGE RELATED MACULAR DEGENERATION; ANTIANGIOGENIC ACTIVITY; BLOOD VESSEL PERMEABILITY; BRANCH RETINAL VEIN OCCLUSION; CARDIOVASCULAR DISEASE; CEREBROVASCULAR ACCIDENT; CONGESTIVE HEART FAILURE; CORNEA NEOVASCULARIZATION; DIABETIC MACULAR EDEMA; DIABETIC RETINOPATHY; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG STRUCTURE; ENDOTHELIUM CELL; EYE DISEASE; GEOGRAPHIC ATROPHY; HEART INFARCTION; HUMAN; LASER-INDUCED CHOROIDAL NEOVASCULARIZATION; LOADING DRUG DOSE; MACULAR EDEMA; METASTASIS; METASTATIC COLORECTAL CANCER; NERVOUS SYSTEM DEVELOPMENT; NEUROPROTECTION; NONHUMAN; OFF LABEL DRUG USE; PHARMACODYNAMICS; PRIORITY JOURNAL; PROLIFERATIVE DIABETIC RETINOPATHY; RECOMMENDED DRUG DOSE; RETINA BLOOD VESSEL; RETINA TEAR; RETINA VEIN OCCLUSION; RETROLENTAL FIBROPLASIA; REVIEW; SINGLE DRUG DOSE; SUBRETINAL NEOVASCULARIZATION; TACHYPHYLAXIS; THROMBOEMBOLISM; UNSPECIFIED SIDE EFFECT; VISUAL ACUITY; VISUAL IMPAIRMENT; ANIMAL; ANTAGONISTS AND INHIBITORS; EYE; NEOVASCULARIZATION, PATHOLOGIC; VASCULARIZATION;

ANGIOGENESIS INHIBITORS; ANIMALS; EYE; HUMANS; NEOVASCULARIZATION, PATHOLOGIC; OLIGONUCLEOTIDES; TACHYPHYLAXIS; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 84950258041     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2015.11.027     Document Type: Review

References (209)

1. N.M. Bressler Age-related macular degeneration is the leading cause of blindness JAMA 291 15 2004 1900 1901
2. S.J. Song, and T.Y. Wong Current concepts in diabetic retinopathy Diabetes Metab. J. 38 6 2014 416 425
3. R.D. Jager, W.F. Mieler, and J.W. Miller Age related macular degeneration N. Engl. J. Med. 358 2008 2606 2617
4. R. Klein Retinopathy in a population-based study Trans. Am. Ophthalmol. Soc. 90 1992 561 594
5. N. Cheung, P. Mitchell, and T.Y. Wong Diabetic retinopathy Lancet 376 9735 2010 124 136
6. D.S. Friedman, M.R. Wilson, J.M. Liebmann, R.D. Fechtner, and R.N. Weinreb An evidence-based assessment of risk factors for the progression of ocular hypertension and glaucoma Am. J. Ophthalmol. 138 Suppl 2004 19 31
7. A. Das, and P.G. McGuire Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition Prog. Retin. Eye Res. 22 6 2003 721 748
8. E. Brylla, G. Tscheudschilsuren, A.N. Santos, K. Nieber, K. Spanel-Borowski, and G. Aust Differences between retinal and choroidal microvascular endothelial cells (MVECs) under normal and hypoxic conditions Exp. Eye Res. 77 5 2003 527 535
9. A. Kvanta Ocular angiogenesis: the role of growth factors Acta Ophthalmol. Scand. 84 3 2006 282 288
10. N. Cheung, I.Y. Wong, and T.Y. Wong Ocular anti-VEGF therapy for diabetic retinopathy: overview of clinical efficacy and evolving applications Diabetes Care 37 4 2014 900 905
11. W.M. Amoaku, U. Chakravarthy, R. Gale, M. Gavin, F. Ghanchi, J. Gibson, S. Harding, R.L. Johnston, S. Kelly, A. Lotery, S. Mahmood, G. Menon, S. Sivaprasad, J. Talks, A. Tufail, and Y. Yang Defining response to anti-VEGF therapies in neovascular AMD Eye (Lond.) 29 6 2015 721 731
12. S.J. McGimpsey, and U. Chakravarthy VEGF-targeted therapy and beyond: pharmacotherapy and emerging treatments in age-related macular degeneration Expert Rev. Clin. Pharmacol. 3 2 2010 243 252
13. M.J. Tolentino, A. Dennrick, E. John, and M.S. Tolentino Drugs in phase II clinical trials for the treatment of age-related macular degeneration Expert Opin. Investig. Drugs 24 2 2015 183 199
14. M.V. Giet, C. Henkel, M. Schuchardt, and M. Tölle Anti-VEGF drugs in eye diseases: local therapy with potential systemic effects Curr. Pharm. Des. 21 24 2015 3548 3556
15. J. Lowe, J. Araujo, J. Yang, M. Reich, A. Oldendorp, V. Shiu, V. Quarmby, H. Lowman, S. Lien, J. Gaudreault, and M. Maia Ranibizumab inhibits multiple forms of biologically active vascular endothelial growth factor in vitro and in vivo Exp. Eye Res. 85 4 2007 425 430
16. FDA Consum, 2006. Treatment for wet macular degeneration. Sep-Oct, 40(5), 6.
17. U. Schmidt-Erfurth, V. Chong, A. Loewenstein, M. Larsen, E. Souied, R. Schlingemann, B. Eldem, J. Monés, G. Richard, F. Bandello, S. European, R. of, and S. etina Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA) Br. J. Ophthalmol. 98 9 2014 1144 1167
18. C. Schmucker, G. Antes, and M. Lelgemann Position paper: the need for head-to-head studies comparing Avastin versus Lucentis Surv. Ophthalmol. 54 6 2009 705 707
19. A.B. Nepomuceno, E. Takaki, F.P. Paes de Almeida, R. Peroni, J.A. Cardillo, R.C. Siqueira, I.U. Scott, A. Messias, and R. Jorge A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema Am. J. Ophthalmol. 156 3 2013 502 510 e2
20. J. Silver Drugs for macular degeneration, price discrimination, and medicare's responsibility not to overpay JAMA 312 1 2014 23 24 Erratum in: JAMA 2014, 312(19), 2045
21. Aflibercept: AVE 0005, AVE 005, AVE0005, VEGF Trap - Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye. Drugs R. D. 2008, 9(4), 261-9.
22. J.A. Dixon, S.C. Oliver, J.L. Olson, and N. Mandava VEGF trap-eye for the treatment of neovascular age-related macular degeneration Expert Opin. Investig. Drugs 18 10 2009 1573 1580
23. F.R. Stefanini, E. Badaró, P. Falabella, M. Koss, M.E. Farah, and M. Maia Anti-VEGF for the management of diabetic macular edema J. Immunol. Res. 632307 2014 10.1155/2014/632307
24. W. Nowak, A. Żarowska, E. Szul-Pietrzak, and M. Misiuk-Hojło System and measurement method for binocular pupillometry to study pupil size variability Biomed. Eng. Online 13 2014 69
25. E.W. Ng, D.T. Shima, P. Calias, E.T. Cunningham Jr.; D.R. Guyer, and A.P. Adamis Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease Nat. Rev. Drug Discov. 5 2 2006 123 132
26. K.A. Houck, N. Ferrara, J. Winer, G. Cachianes, B. Li, and D.W. Leung The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA Mol. Endocrinol. 5 12 1991 1806 1814
27. E. Tischer, R. Mitchell, T. Hartman, M. Silva, D. Gospodarowicz, J.C. Fiddes, and J.A. Abraham The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing J. Biol. Chem. 266 18 1991 11947 11954
28. N. Ferrara, H.P. Gerber, and J. LeCouter The biology of VEGF and its receptors Nat. Med. 9 6 2003 669 676
29. D.O. Bates, T.G. Cui, J.M. Doughty, M. Winkler, M. Sugiono, J.D. Shields, D. Peat, D. Gillatt, and S.J. Harper VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma Cancer Res. 62 14 2002 4123 4131
30. T. Usui, S. Ishida, K. Yamashiro, Y. Kaji, V. Poulaki, J. Moore, T. Moore, S. Amano, Y. Horikawa, D. Dartt, M. Golding, D.T. Shima, and A.P. Adamis VEGF164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2 Invest. Ophthalmol. Vis. Sci. 45 2 2004 368 374
31. A. Muthusamy, C.M. Lin, S. Shanmugam, H.M. Lindner, S.F. Abcouwer, and D.A. Antonetti Ischemia-reperfusion injury induces occludin phosphorylation/ubiquitination and retinal vascular permeability in a VEGFR-2-dependent manner J. Cereb. Blood Flow Metab. 34 3 2014 522 531
32. S. Soker, S. Takashima, H.Q. Miao, G. Neufeld, and M. Klagsbrun Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor Cell 92 6 1998 735 745
33. S.J. Harper, and D.O. Bates VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat. Rev. Cancer 8 11 2008 880 887
34. H. Kawamura, X. Li, S.J. Harper, D.O. Bates, and L. Claesson-Welsh Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity Cancer Res. 68 12 2008 4683 4692
35. S. Djordjevic, and P.C. Driscoll Targeting VEGF signalling via the neuropilin co-receptor Drug Discov. Today 18 9-10 2013 447 455
36. M. Tolentino Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease Surv. Ophthalmol. 56 2011 95 113
37. S. Lee, T.T. Chen, C.L. Barber, M.C. Jordan, J. Murdock, S. Desai, N. Ferrara, A. Nagy, K.P. Roos, M.L. Iruela-Arispe, and V.E.G.F. Autocrine signaling is required for vascular homeostasis Cell 130 4 2007 691 703
38. F. Baffert, T. Le, B. Sennino, G. Thurston, C.J. Kuo, D. Hu-Lowe, and D.M. McDonald Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling Am. J. Physiol. Heart Circ. Physiol. 290 2 2006 H547 H559
39. P. Vempati, A.S. Popel, G. Mac, and F. abhann Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning Cytokine Growth Factor Rev. 25 1 2014 1 19
40. P. Carmeliet, and D. Collen Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development Curr. Top. Microbiol. Immunol. 237 1999 133 158
41. I. Stalmans, Y.S. Ng, R. Rohan, M. Fruttiger, A. Bouché, A. Yuce, H. Fujisawa, B. Hermans, M. Shani, S. Jansen, D. Hicklin, D.J. Anderson, T. Gardiner, H.P. Hammes, L. Moons, M. Dewerchin, D. Collen, P. Carmeliet, and P.A. D'Amore Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms J. Clin. Invest. 109 3 2002 327 336
42. S. Ishida, T. Usui, K. Yamashiro, Y. Kaji, S. Amano, Y. Ogura, T. Hida, Y. Oguchi, J. Ambati, J.W. Miller, E.S. Gragoudas, Y.S. Ng, P.A. D'Amore, D.T. Shima, and A.P. Adamis VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization J. Exp. Med. 198 3 2003 483 489
43. C. Ruhrberg, H. Gerhardt, M. Golding, R. Watson, S. Ioannidou, H. Fujisawa, C. Betsholtz, and D.T. Shima Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis Genes Dev. 16 20 2002 2684 2698
44. C. Ruhrberg Growing and shaping the vasculartree: multiple roles for VEGF Bioessays 25 11 2003 1052 1060
45. H. Gerhardt, M. Golding, M. Fruttiger, C. Ruhrberg, A. Lundkvist, A. Abramsson, M. Jeltsch, C. Mitchell, K. Alitalo, D. Shima, and C. Betsholtz VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia J. Cell Biol. 161 6 2003 1163 1177
46. H. Gerhardt VEGF and endothelial guidance in angiogenic sprouting Organogenesis 4 4 2008 241 246
47. M. Saint-Geniez, A.E. Maldonado, and P.A. D'Amore VEGF expression and receptor activation in the choroid during development and in the adult Invest. Ophthalmol. Vis. Sci. 47 7 2006 3135 3142
48. M. Saint-Geniez, T. Kurihara, E. Sekiyama, A.E. Maldonado, and P.A. D'Amore An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris Proc. Natl. Acad. Sci. U. S. A. 106 44 2009 18751 18756
49. C.N. Nagineni, V.K. Kommineni, A. William, B. Detrick, and J.J. Hooks Regulation of VEGF expression in human retinal cells by cytokines: implications for the role of inflammation in age-related macular degeneration J. Cell. Physiol. 227 1 2012 116 126
50. B.A. Keyt, L.T. Berleau, H.V. Nguyen, H. Chen, H. Heinsohn, R. Vandlen, and N. Ferrara The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency J. Biol. Chem. 271 13 1996 7788 7789
51. G.B. Whitaker, B.J. Limberg, and J.S. Rosenbaum Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121) J. Biol. Chem. 276 27 2001 25520 25531
52. E. Storkebaum, D. Lambrechts, and P.V.E.G.F. Carmeliet once regarded as a specific angiogenic factor, now implicated in neuroprotection Bioessays 26 9 2004 943 954
53. D.A. Greenberg, and K. Jin From angiogenesis to neuropathology Nature 438 7070 2005 954 959
54. D. Lambrechts, and P. Carmeliet VEGF at the neurovascular interface: therapeutic implications for motor neuron disease Biochim. Biophys. Acta 1762 11-12 2006 1109 1121
55. K.L. Jin, X.O. Mao, and D.A. Greenberg Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia Proc. Natl. Acad. Sci. U. S. A. 97 18 2000 10242 10247
56. J.M. Rosenstein, N. Mani, A. Khaibullina, and J.M. Krum Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons J. Neurosci. 23 35 2003 11036 11044
57. I. Zachary Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential Neurosignals 14 5 2005 207 221
58. F.Y. Sun, and X. Guo Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor J. Neurosci. Res. 79 1-2 2005 180 184
59. J.N. Nicoletti, S.K. Shah, D.P. McCloskey, J.H. Goodman, A. Elkady, H. Atassi, D. Hylton, J.S. Rudge, H.E. Scharfman, and S.D. Croll Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus Neuroscience 151 1 2008 232 241
60. W.F. Silverman, J.M. Krum, N. Mani, and J.M. Rosenstein Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explantcultures Neuroscience 90 1999 1529 1541
61. K. Nishijima, Y.S. Ng, L. Zhong, J. Bradley, W. Schubert, N. Jo, J. Akita, S.J. Samuelsson, G.S. Robinson, A.P. Adamis, and D.T. Shima Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury Am. J. Pathol. 171 1 2007 53 67
62. S. Singh, and T.W. Evans Nitric oxide, the biological mediator of the decade: fact or fiction? Eur. Respir. J. 10 3 1997 699 707
63. E. Martínez-Vila, and P.I. Sieira Current status and perspectives of neuroprotection in ischemic stroke treatment Cerebrovasc. Dis. 11 Suppl. 1 2001 60 70
64. R.H. Foxton, A. Finkelstein, S. Vijay, A. Dahlmann-Noor, P.T. Khaw, J.E. Morgan, D.T. Shima, and Y.S. Ng VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma Am. J. Pathol. 182 4 2013 1379 1390
65. R.M. Perrin, O. Konopatskaya, Y. Qiu, S. Harper, D.O. Bates, and A.J. Churchill Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor Diabetologia 48 11 2005 2422 2427
66. J. Hua, C. Spee, S. Kase, E.S. Rennel, A.L. Magnussen, Y. Qiu, A. Varey, S. Dhayade, A.J. Churchill, S.J. Harper, D.O. Bates, and D.R. Hinton Recombinant human VEGF165b inhibits experimental choroidal neovascularization Invest. Ophthalmol. Vis. Sci. 51 8 2010 4282 4288
67. Z. Zhao, Y. Chen, J. Wang, P. Sternberg, M.L. Freeman, H.E. Grossniklaus, and J. Cai Age-related retinopathy in NRF2-deficient mice PLoS One 6 4 2011 e19456
68. C. Ehlken, E.S. Rennel, D. Michels, B. Grundel, A. Pielen, B. Junker, A. Stahl, L.L. Hansen, N. Feltgen, H.T. Agostini, and G. Martin Levels of VEGF but not VEGF(165b) are increased in the vitreous of patients with retinal vein occlusion Am. J. Ophthalmol. 152 2 2011 298 303 e1
69. T. Baba, G. Bikbova, M. Kitahashi, H. Yokouchi, T. Oshitari, and S. Yamamoto Level of vascular endothelial growth factor 165b in human aqueous humor Curr. Eye Res. 39 8 2014 830 836
70. O. Konopatskaya, A.J. Churchill, S.J. Harper, D.O. Bates, and T.A. Gardiner VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice Mol. Vis. 12 2006 626 632
71. A.L. Magnussen, E.S. Rennel, J. Hua, H.S. Bevan, N. Beazley Long, C. Lehrling, M. Gammons, S.J. FloegeJ. Harper, H.T. Agostini, D.O. Bates, and A.J. Churchill VEGF-A165b is cytoprotective and antiangiogenic in the retina Invest. Ophthalmol. Vis. Sci. 51 8 2010 4273 4281
72. E.S. Rennel, E. Waine, H. Guan, Y. Schüler, W. Leenders, J. Woolard, M. Sugiono, D. Gillatt, E. Kleinerman, D. Bates, and S. Harper The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice Br. J. Cancer 98 7 2008 1250 1257
73. E.S. Rennel, M.A. Hamdollah-Zadeh, E.R. Wheatley, A. Magnussen, Y. Schüler, S.P. Kelly, C. Finucane, D. Ellison, S. Cebe-Suarez, K. Ballmer-Hofer, S. Mather, L. Stewart, D.O. Bates, and S.J. Harper Recombinant human VEGF165b protein is an effective anti-cancer agent in mice Eur. J. Cancer 44 13 2008 1883 1894
74. J. Woolard, W.Y. Wang, H.S. Bevan, Y. Qiu, L. Morbidelli, R.O. Pritchard-Jones, T.G. Cui, W. SugionoM, E. aine, R. Perrin, R. Foster, J. Digby-Bell, J.D. Shields, C.E. Whittles, R.E. Mushens, D.A. Gillatt, M. Ziche, S.J. Harper, and D.O. Bates VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression Cancer Res. 64 21 2004 7822 7835
75. N. Beazley-Long, J. Hua, T. Jehle, R.P. Hulse, R. Dersch, C. Lehrling, H. Bevan, Y. Qiu, W.A. Lagrèze, D. Wynick, A.J. Churchill, P. Kehoe, S.J. Harper, D.O. Bates, and L.F. Donaldson VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro Am. J. Pathol. 183 3 2013 918 929
76. D. Jellinek, L.S. Green, C. Bell, and N. Janjić Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth factor Biochemistry 33 34 1994 10450 10456
77. C. Tuerk, and L. Gold Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase Science 249 4968 1990 505 510
78. D.R. Senger, S.J. Galli, A.M. Dvorak, C.A. Perruzzi, V.S. Harvey, and H.F. Dvorak Tumor cells secrete a vascular permeability factor that promotes accumulation of ascitesfluid Science 219 4587 1983 983 985
79. D.W. Leung, G. Cachianes, W.J. Kuang, D.V. Goeddel, and N. Ferrara Vascular endothelial growth factor is a secreted angiogenic mitogen Science 246 4935 1989 1306 1309
80. P.J. Keck, S.D. Hauser, G. Krivi, K. Sanzo, T. Warren, J. Feder, and D.T. Connolly Vascular permeability factor, an endothelial cell mitogen related to PDGF Science 246 4935 1989 1309 1312
81. K.J. Kim, B. Li, J. Winer, M. Armanini, N. Gillett, H.S. Phillips, and N. Ferrara Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo Nature 362 6423 1993 841 844
82. R.L. Kendall, and K.A. Thomas Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor Proc. Natl. Acad. Sci. U. S. A. 90 22 1993 10705 10709
83. L.S. Green, D. Jellinek, C. Bell, L.A. Beebe, B.D. Feistner, S.C. Gill, F.M. Jucker, and N. Janjić Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor Chem. Biol. 2 10 1995 683 695
84. J. Ruckman, L.S. Green, J. Beeson, S. Waugh, W.L. Gillette, D.D. Henninger, L. Claesson-Welsh, and N. Janjić 2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain J. Biol. Chem. 273 32 1998 20556 20567
85. J.M. Healy, S.D. Lewis, M. Kurz, R.M. Boomer, K.M. Thompson, C. Wilson, and T.G. McCauley Pharmacokinetics and biodistribution of novel aptamer compositions Pharm. Res. 21 12 2004 2234 2246
86. C. Bell, E. Lynam, D.J. Landfair, N. Janjic, and M.E. Wiles Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro In Vitro Cell. Dev. Biol. Anim. 35 9 1999 533 542
87. Eyetech Study Group Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration Retina 22 2 2002 143 152
88. J.H. Lee, M.D. Canny, A. De Erkenez, D. Krilleke, Y.S. Ng, D.T. Shima, A. Pardi, and F. Jucker A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165 Proc. Natl. Acad. Sci. U. S. A. 102 52 2005 18902 18907
89. T. Hermann, and D.J. Patel Adaptive recognition by nucleic acid aptamers Science 287 5454 2000 820 825
90. D.O. Bates, A. Mavrou, Y. Qiu, J.G. Carter, M. Hamdollah-Zadeh, S. Barratt, M.V. Gammons, A.B. Millar, A.H. Salmon, S. Oltean, and S.J. Harper Detection of VEGF-A(xxx) b isoforms in human tissues PLoS One 8 7 2013 e68399
91. A.H. Varey, E.S. Rennel, Y. Qiu, H.S. Bevan, R.M. Perrin, S. Raffy, A.R. Dixon, C. Paraskeva, O. Zaccheo, A.B. Hassan, S.J. Harper, and D.O. Bates VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy Br. J. Cancer 98 8 2008 1366 1379
92. A. Klettner, and J. Roider Comparison of bevacizumab, ranibizumab, and pegaptanib in vitro: efficiency and possible additional pathways Invest. Ophthalmol. Vis. Sci. 49 10 2008 4523 4527
93. L.G. Presta, H. Chen, S.J. O'Connor, V. Chisholm, Y.G. Meng, L. Krummen, M. Winkler, and N. Ferrara Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders Cancer Res. 57 20 1997 4593 4599
94. E.S. Gragoudas, A.P. Adamis, E.T. Cunningham Jr.; M. Feinsod, and D.R. Guyer VEGF inhibition study in ocular neovascularization clinical trial group. Pegaptanib for neovascular age-related macular degeneration N. Engl. J. Med. 351 27 2004 2805 2816
95. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, U. Chakravarthy, A.P. Adamis, E.T. Cunningham Jr.; M. Goldbaum, D.R. Guyer, B. Katz, and M. Patel Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration Ophthalmology 113 9 2006 1508 e1-e25
96. C.R. Gonzales, and VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis Retina 25 7 2005 815 827
97. P.A. Quiram, T.S. Hassan, and G.A. Williams Treatment of naïve lesions in neovascular age-related macular degeneration with pegaptanib Retina 27 7 2007 851 856
98. Y. Nishimura, M. Taguchi, T. Nagai, M. Fujihara, S. Honda, and M. Uenishi Comparison of the effect between pegaptanib and ranibizumab on exudative age-related macular degeneration with small lesion size Clin. Ophthalmol. 6 2012 365 368
99. M.S. Hughes, and D.N. Sang Safety and efficacy of intravitreal bevacizumab followed by pegaptanib maintenance as a treatment regimen for age-related macular degeneration Ophthalmic. Surg. Lasers Imaging 37 6 2006 446 454
100. T.R. Friberg, M. Tolentino, LEVEL Study Group, P. Weber, S. Patel, S. Campbell, and M. Goldbaum Pegaptanib sodium as maintenance therapy in neovascular age-related macular degeneration: the LEVEL study Br. J. Ophthalmol. 94 12 2010 1611 1617
101. T. Ishibashi, and LEVEL-J Study Group Maintenance therapy with pegaptanib sodium for neovascular age-related macular degeneration: an exploratory study in Japanese patients (LEVEL-J study) Jpn. J. Ophthalmol. 57 5 2013 417 423
102. M. Inoue, K. Kadonosono, A. Arakawa, S. Yamane, and T. Ishibashi Long-term outcome of intravitreal pegaptanib sodium as maintenance therapy in Japanese patients with neovascular age-related macular degeneration Jpn. J. Ophthalmol. 59 3 2015 173 178
103. A.P. Adamis, M. Altaweel, N.M. Bressler, E.T. Cunningham Jr, M.D. Davis, M. Goldbaum, C. Gonzales, D.R. Guyer, K. Barrett, and M. Patel Macugen diabetic retinopathy study group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals Ophthalmology 113 1 2006 23 28
104. G. Querques, A.V. Bux, D. Martinelli, C. Iaculli, and N.D. Noci Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema Acta Ophthalmol. 87 6 2009 623 630
105. A. Salam, R. Mathew, and S. Sivaprasad Treatment of proliferative diabetic retinopathy with anti-VEGF agents Acta Ophthalmol. 89 5 2011 405 411
106. M. Rinaldi, F. Chiosi, R. DellOmo, M.R. Romano, F. Parmeggiani, F. Semeraro, M. Menzione, and C. Costagliola Intravitreal pegaptanib sodium (Macugen) for treatment of myopic choroidal neovascularization: a morphologic and functional study Retina 33 2 2013 397 402
107. M.J. Martìnez-Zapata, A.J. Martí-Carvajal, I. Solà, J.I. Pijoán, J.A. Buil-Calvo, J.A. Cordero, and J.R. Evans Anti-vascular endothelial growth factor for proliferative diabetic retinopathy Cochrane Database Syst. Rev. 11 2014 CD008721
108. G. Virgili, M. Parravano, F. Menchini, and J.R. Evans Anti-vascular endothelial growth factor for diabetic macular oedema Cochrane Database Syst. Rev. 10 2014 CD007419
109. T. Braithwaite, A.A. Nanji, K. Lindsley, and P.B. Greenberg Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion Cochrane Database Syst. Rev. 5 2014 CD007325
110. D.M. Brown, M. Michels, P.K. Kaiser, J.S. Heier, J.P. Sy, T. Ianchulev, and ANCHOR Study Group Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study Ophthalmology 116 1 2009 57 65 e5
111. CATT Research Group, D.F. Martin, M.G. Maguire, G.S. Ying, J.E. Grunwald, S.L. Fine, and G.J. Jaffe Ranibizumab and bevacizumab for neovascular age-related macular degeneration N. Engl. J. Med. 364 20 2011 1897 1908
112. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, D.F. Martin, M.G. Maguire, S.L. Fine, G.S. Ying, G.J. Jaffe, J.E. Grunwald, C. Toth, M. Redford, and F.L. Ferris 3rd. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results Ophthalmology 119 7 2012 1388 1398
113. U. Chakravarthy, S.P. Harding, C.A. Rogers, S.M. Downes, A.J. Lotery, L.A. Culliford, and B.C. Reeves IVAN study investigators. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial Lancet 382 9900 2013 1258 1267
114. P.J. Rosenfeld, D.M. Brown, J.S. Heier, D.S. Boyer, P.K. Kaiser, C.Y. Chung, R.Y. Kim, and MARINA Study Group Ranibizumab for neovascular age-related macular degeneration N. Engl. J. Med. 355 14 2006 1419 1431
115. M.A. Singer, C.C. Awh, S. Sadda, W.R. Freeman, A.N. Antoszyk, P. Wong, and L. Tuomi HORIZON an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration Ophthalmology 119 6 2012 1175 1183
116. T. Inai, M. Mancuso, H. Hashizume, F. Baffert, A. Haskell, P. Baluk, D.D. Hu-Lowe, D.R. Shalinsky, G. Thurston, G.D. Yancopoulos, and D.M. McDonald Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts Am. J. Pathol. 165 1 2004 35 52
117. T. Kamba, B.Y. Tam, H. Hashizume, A. Haskell, B. Sennino, M.R. Mancuso, S.M. Norberg, S.M. O'Brien, R.B. Davis, L.C. Gowen, K.D. Anderson, G. Thurston, S. Joho, M.L. Springer, C.J. Kuo, and D.M. McDonald VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature Am. J. Physiol. Heart Circ. Physiol. 290 2 2006 H560 H576
118. K.G. Falavarjani, and Q.D. Nguyen Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature Eye (Lond.) 27 7 2013 787 794
119. C. Biagi, V. Conti, N. Montanaro, M. Melis, E. Buccellato, M. Donati, A. Covezzoli, R. Amato, L. Pazzi, M. Venegoni, A. Vaccheri, and D. Motola Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO database of adverse drug reactions Eur. J. Clin. Pharmacol. 70 12 2014 1505 1512
120. A. Penedones, D. Mendes, C. Alves, M. Batel, and F. arques Safety monitoring of ophthalmic biologics: a systematic review of pre- and postmarketing safety data J. Ocul. Pharmacol. Ther. 30 9 2014 729 751
121. P.J. Rosenfeld, H. Shapiro, L. Tuomi, M. Webster, J. Elledge, B. Blodi, and MARINA and ANCHOR Study Groups Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials Ophthalmology 118 3 2011 523 530
122. N. Lois, V. McBain, E. Abdelkader, N.W. Scott, and R. Kumari Retinal pigment epithelial atrophy in patients with exudative age-related macular degeneration undergoing anti-vascular endothelial growth factor therapy Retina 33 1 2013 13 22
123. I. Bhutto, and G. Lutty Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex Mol. Aspects Med. 33 4 2012 295 317
124. F.G. Holz, E.C. Strauss, S. Schmitz-Valckenberg, and M. van Lookeren Campagne Geographic atrophy: clinical features and potential therapeutic approaches Ophthalmology 121 5 2014 1079 1091
125. J.E. Grunwald, E. Daniel, J. Huang, G.S. Ying, M.G. Maguire, C.A. Toth, G.J. Jaffe, S.L. Fine, B. Blodi, M.L. Klein, A.A. Martin, S.A. Hagstrom, D.F. Martin, and CATT Research Group Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials Ophthalmology 121 1 2014 150 161
126. J.E. Grunwald, M. Pistilli, G.S. Ying, M.G. Maguire, E. Daniel, and D.F. Martin Comparison of age-related macular degeneration treatments trials research group. Growth of geographic atrophy in the comparison of age-related macular degeneration treatments trials Ophthalmology 122 4 2015 809 816
127. S. Rofagha, R.B. Bhisitkul, D.S. Boyer, S.R. Sadda, K. Zhang, and SEVEN-UP Study Group Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON a multicenter cohort study (SEVEN-UP) Ophthalmology 120 11 2013 2292 2299
128. G. Querques, A.V. Bux, and N. Delle Noci Foveal geographic atrophy following intravitreal pegaptanib sodium (Macugen) for drusenoid pigment epithelium detachment Eur. J. Ophthalmol. 19 5 2009 890 893
129. M. Gutfleisch, B. Heimes, M. Schumacher, M. Dietzel, A. Lommatzsch, A. Bird, and D. Pauleikhoff Long-term visual outcome of pigment epithelial tears in association with anti-VEGF therapy of pigment epithelial detachment in AMD Eye (Lond.) 25 9 2011 1181 1186
130. E. Daniel, C.A. Toth, J.E. Grunwald, G.J. Jaffe, D.F. Martin, S.L. Fine, J. Huang, G.S. Ying, S.A. Hagstrom, K. Winter, and M.G. Maguire Comparison of age-related macular degeneration treatments trials research group. Risk of scar in the comparison of age-related macular degeneration treatments trials Ophthalmology 121 3 2014 656 666
131. L.K. Chang, and D. Sarraf Tears of the retinal pigment epithelium: an old problem in a new era Retina 27 5 2007 523 534
132. S. Doguizi, and S. Ozdek Pigment epithelial tears associated with anti-VEGF therapy: incidence, long-term visual outcome, and relationship with pigment epithelial detachment in age-related macular degeneration Retina 34 6 2014 1156 1162
133. D. Sarraf, A. Joseph, and E. Rahimy Retinal pigment epithelial tears in the era of intravitreal pharmacotherapy: risk factors, pathogenesis, prognosis and treatment (an American Ophthalmological Society thesis) Trans. Am. Ophthalmol. Soc. 112 2014 142 159
134. Z. Li, T. Van Bergen, S. Van de Veire, I. Van de Vel, H. Moreau, M. Dewerchin, P.C. Maudgal, T. Zeyen, W. Spileers, L. Moons, and I. Stalmans Inhibition of vascular endothelial growth factor reduces scar formation after glaucoma filtration surgery Invest. Ophthalmol. Vis. Sci. 50 11 2009 5217 5225
135. T. Van Bergen, E. Vandewalle, S. Van de Veire, M. Dewerchin, J.M. Stassen, L. Moons, and I. Stalmans The role of different VEGF isoforms in scar formation after glaucoma filtration surgery Exp. Eye Res. 93 5 2011 689 699
136. ®) in neovascular age-related macular degeneration Acta Ophthalmol. 88 6 2010 641 645
137. D.N. Papadopoulou, E. Mendrinos, G. Mangioris, G. Donati, and C.J. Pournaras Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration Ophthalmology 116 9 2009 1755 1761
138. P. Bonnin, J.A. Pournaras, K. Makowiecka, V. Krivosic, A.W. Kedra, G. Le, J.F. argasson, A. Gaudric, B.I. Levy, Y.S. Cohen, R. Tadayoni, and P. Massin Ultrasound assessment of ocular vascular effects of repeated intravitreal injections of ranibizumab for wet age-related macular degeneration Acta Ophthalmol. 92 5 2014 e382 e387
139. ®) injection on retinal and retrobulbar blood flow in retinal Ischaemic diseases Acta Ophthalmol. 93 August (5) 2015 e399 e400
140. H. Kim, S.B. Robinson, and K.G. Csaky FcRn receptor-mediated pharmacokinetics of therapeutic IgG in the eye Mol. Vis. 15 2009 2803 2812
141. K. Matsuyama, N. Ogata, M. Matsuoka, M. Wada, K. Takahashi, and T. Nishimura Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab Br. J. Ophthalmol. 94 9 2010 1215 1218
142. S.R. Hayman, N. Leung, J.P. Grande, and V.D. Garovic VEGF inhibition, hypertension, and renal toxicity Curr. Oncol. Rep. 14 4 2012 285 294
143. Y. Duan, J. Mo, R. Klein, I.U. Scott, H.M. Lin, J. Caulfield, M. Patel, and D. Liao Age-related macular degeneration is associated with incident myocardial infarction among elderly Americans Ophthalmology 114 4 2007 732 737
144. J. Tuñón, J.M. Ruiz-Moreno, J.L. Martìn-Ventura, L.M. Blanco-Colio, O. Lorenzo, and J. Egido Cardiovascular risk and antiangiogenic therapy for agerelated macular degeneration Surv. Ophthalmol. 54 3 2009 339 348
145. L.H. Curtis, B.G. Hammill, K.A. Schulman, and S.W. Cousins Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration Arch. Ophthalmol. 128 10 2010 1273 1279
146. M.K. Ikram, P. Mitchell, R. Klein, A.R. Sharrett, D.J. Couper, and T.Y. Wong Age-related macular degeneration and long-term risk of stroke subtypes Stroke 43 6 2012 1681 1683
147. Mancia, ESH/ESC Task Force for the Management of Arterial Hypertension, and et al. Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension J. Hypertens 31 10 2013 1925 1938
148. L. Krause, T. Yousif, K. Pohl, and CAPTAIN study group An epidemiological study of neovascular age-related macular degeneration in Germany Curr. Med. Res. Opin. 29 10 2013 1391 1397
149. T.Y. Wong, R. Klein, C. Sun, P. Mitchell, D.J. Couper, H. Lai, L.D. Hubbard, and A.R. Sharrett Atherosclerosis risk in communities study. Age-related macular degeneration and risk of stroke Ann. Intern. Med. 145 2 2006 98 107
150. F. Semeraro, F. Morescalchi, S. Duse, E. Gambicorti, M.R. Romano, and C. Costagliola Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview Expert Opin. Drug Saf. 13 6 2014 785 802
151. L.J. Singerman, H. Masonson, M. Patel, A.P. Adamis, R. Buggage, E. Cunningham, M. Goldbaum, B. Katz, and D. Guyer Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial Br. J. Ophthalmol. 92 2008 1606 1611
152. V. Chong Biological, preclinical and clinical characteristics of inhibitors of vascular endothelial growth factors Ophthalmologica 227 Suppl. 1 2012 2 10
153. R. Morjaria, and N.V. Chong Pharmacokinetic evaluation of pegaptanib octasodium for the treatment of diabetic edema Expert Opin. Drug Metab. Toxicol. 10 8 2014 1185 1192
154. A.A. Zachary, R.A. Montgomery, and M.S. Leffell Factors associated with and predictive of persistence of donor-specific antibody after treatment with plasmapheresis and intravenous immunoglobulin Hum. Immunol. 66 4 2005 364 370
155. N.M. Bressler, D.S. Boyer, D.F. Williams, S. Butler, S.F. Francom, B. Brown, F. Di Nucci, T. Cramm, L.L. Tuomi, T. Ianchulev, and R.G. Rubio Cerebrovascular accidents in patients treated for choroidal neovascularization with ranibizumab in randomized controlled trials Retina 32 9 2012 1821 1828
156. T. Ueta, Y. Noda, T. Toyama, T. Yamaguchi, and S. Amano Systemic vascular safety of ranibizumab for age-related macular degeneration: systematic review and meta-analysis of randomized trials Ophthalmology 121 11 2014 2193 2203 e1-e7
157. A. Verheyen, E. Peeraer, R. Nuydens, J. Dhondt, K. Poesen, I. Pintelon, A. Daniels, J.P. Timmermans, T. Meert, P. Carmeliet, and D. Lambrechts Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy Brain 135 2012 2629 2641
158. R.P. Hulse, N. Beazley-Long, J. Hua, H. Kennedy, J. Prager, H. Bevan, Y. Qiu, E.S. Fernandes, M.V. Gammons, K. Ballmer-Hofer, Gittenberger, A.C. de Groot, A.J. Churchill, S.J. Harper, S.D. Brain, D.O. Bates, and L.F. Donaldson Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia Neurobiol. Dis. 71 2014 245 259
159. X. Zhu, S. Wu, W.L. Dahut, and C.R. Parikh Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis Am. J. Kidney Dis. 49 2007 186 193
160. S.R. Hayman, N. Leung, J.P. Grande, and V.D. Garovic VEGF inhibition, hypertension, and renal toxicity Curr. Oncol. Rep. 14 4 2012 285 294
161. Y. Kitamoto, H. Tokunaga, K. Miyamoto, and K. Tomita VEGF is an essential molecule for glomerular structuring Nephrol. Dial. Transplant. 17 Suppl. 9 2002 25 27
162. V. Eremina, and S.E. Quaggin The role of VEGF-A in glomerular development and function Curr. Opin. Nephrol. Hypertens 13 1 2004 9 15
163. S. Suga, Y.G. Kim, A. Joly, E. Puchacz, D.H. Kang, J.A. Jefferson, J.A. Abraham, J. Hughes, R.J. Johnson, and G.F. Schreiner Vascular endothelial growth factor (VEGF121) protects rats from renal infarction in thrombotic microangiopathy Kidney Int. 60 4 2001 1297 1308
164. F. Feihl, L. Liaudet, B. Waeber, and B.I. Levy Hypertension a disease of the microcirculation? Hypertension 48 2006 1012 1017
165. P. Neri, C. Mariotti, I. Arapi, E. Bambini, and A. Giovannini Anti vascular endothelial growth factor sequential therapy for neovascular age-related macular degeneration: is this the new deal? Curr. Med. Res. Opin. 28 3 2012 395 400
166. C. Ehlken, S. Jungmann, D. Böhringer, H.T. Agostini, B. Junker, and A. Pielen Switch of anti-VEGF agents is an option for nonresponders in the treatment of AMD Eye (Lond.) 28 5 2014 538 545
167. S. Binder Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br. J. Ophthalmol. 96 1 2012 1 2
168. P.A. Keane, S. Liakopoulos, S.C. Ongchin, F.M. Heussen, S. Msutta, K.T. Chang, A.C. Walsh, and S.R. Sadda Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related macular degeneration Invest. Ophthalmol. Vis. Sci. 49 7 2008 3115 3120
169. S. Schaal, H.J. Kaplan, and T.H. Tezel Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 115 12 2008 2199 2205
170. F. Forooghian, C. Cukras, C.B. Meyerle, E.Y. Chew, and W.T. Wong Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration Retina 29 6 2009 723 731
171. P.J. Rosenfeld, D.M. Brown, J.S. Heier, D.S. Boyer, P.K. Kaiser, C.Y. Chung, and R.Y. Kim Ranibizumab for neovascular agerelated macular degeneration N. Engl. J. Med. 355 2006 1419 1431
172. F. Forooghian, E.Y. Chew, C.B. Meyerle, C. Cukras, and W.T. Wong Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis Acta Ophthalmol. 89 2 2011 e206 e207
173. F. Abedi, S. Wickremasinghe, A.J. Richardson, E. Makalic, D.F. Schmidt, S.S. Sandhu, P.N. Baird, and R.H. Guymer Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration Ophthalmology 120 1 2013 115 121
174. K.E. Stepien, P.J. Rosenfeld, C.A. Puliafito, W. Feuer, W. Shi, L. Al-Attar, S.R. Dubovy, T.G. Murray, J.L. Davis, W.H. Lee, S.G. Schwartz, W.E. Smiddy, A.M. Berrocal, and H.W. Flynn Jr. Comparison of intravitreal bevacizumab followed by ranibizumab for the treatment of neovascular age-related macular degeneration Retina 29 8 2009 1067 1073
175. A. Almony, A. Mansouri, G.K. Shah, and K.J. Blinder Efficacy of intravitreal bevacizumab after unresponsive treatment with intravitreal ranibizumab Can. J. Ophthalmol. 46 2 2011 182 185
176. N. Kumar, M. Marsiglia, S. Mrejen, A.T. Fung, J. Slakter, J. Sorenson, and K.B. Freund Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration Retina 33 8 2013 1605 1612
177. C. Shiragami, A. Ono, M. Kobayashi, S. Manabe, A. Yamashita, and F. Shiraga Effect of switching therapy to pegaptanib in eyes with the persistent cases of exudative age-related macular degeneration Medicine (Baltimore) 93 18 2014 e116
178. N. Jo, C. Mailhos, M. Ju, E. Cheung, J. Bradley, K. Nishijima, G.S. Robinson, A.P. Adamis, and D.T. Shima 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 6 2006 2036 2053
179. P. Lindahl, B.R. Johansson, P. Leveen, and C. Betsholtz Pericyte loss and microaneurysm formation in PDGF-B-deficient mice Science 277 1997 242 245
180. M. Ishikawa, D. Jin, Y. Sawada, S. Abe, and T. Yoshitomi Future therapies of wet age-related macular degeneration J. Ophthalmol. 2015 2015 138070
181. M. Amadio, C. Bucolo, G.M. Leggio, F. Drago, S. Govoni, and A. Pascale The PKCbeta/HuR/VEGF pathway in diabetic retinopathy Biochem. Pharmacol. 80 2010 1230 1237
182. M. Amadio, C. Bucolo, S. Govoni, F. Drago, V. D'Agata, A.G. D'Amico, S. Cupri, R. Pignatello, and A. Pascale Interventions against VEGF overexpression, available strategies and future developments Acta Ophthalmol. 93 S255 2015 10.1111/j.1755-3768.2015.0443
183. J. Viiri, M. Amadio, N. Marchesi, J.M. Hyttinen, N. Kivinen, R. Sironen, K. Rilla, S. Akhtar, A. Provenzani, V.G. D'Agostino, S. Govoni, A. Pascale, H. Agostini, G. Petrovski, A. Salminen, and K. Kaarniranta Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells PLoS One 8 2013
184. A. Sene, D. Chin-Yee, and R.S. Apte Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye Trends Mol. Med. 21 1 2015 43 51
185. A. Agarwal, W.R. Rhoades, M. Hanout, M.K. Soliman, S. Sarwar, M.A. Sadiq, Y.J. Sepah, D.V. Do, and Q.D. Nguyen Management of neovascular age-related macular degeneration: current state-of-the-art care for optimizing visual outcomes and therapies in development Clin. Ophthalmol. 9 2015 1001 1015
186. K. Horie-Inoue, and S. Inoue Genomic aspects of age-related macular degeneration Biochem. Biophys. Res. Commun. 452 2 2014 263 275
187. Z. Hu, P. Xie, Y. Ding, D. Yuan, and Q. Liu Association between variants A69S in ARMS2 gene and response to treatment of exudative AMD: a meta-analysis Br. J. Ophthalmol. 99 5 2015 593 598
188. J.R. Kanwar, J.S. Shankaranarayanan, S. Gurudevan, and R.K. Kanwar Aptamer-based therapeutics of the past, present and future: from the perspective of eye-related diseases Drug Discov. Today 19 9 2014 1309 1321
189. S. Chen, J. Feng, L. Ma, Z. Liu, and W. Yuan RNA interference technology for anti-VEGF treatment Expert Opin. Drug Deliv. 11 9 2014 1471 1480
190. N.S. Dejneka, S. Wan, O.S. Bond, D.J. Kornbrust, and S.J. Reich Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes Mol. Vis. 14 2008 997 1005
191. S.J. Reich, J. Fosnot, A. Kuroki, W. Tang, X. Yang, A.M. Maguire, J. Bennett, and M.J. Tolentino Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model Mol. Vis. 9 2003 210 216
192. M.J. Tolentino, A.J. Brucker, J. Fosnot, G.S. Ying, I.H. Wu, G. Malik, S. Wan, and S.J. Reich Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization Retina 24 1 2004 132 138
193. N.S. Dejneka, S. Wan, O.S. Bond, D.J. Kornbrust, and S.J. Reich Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes Mol. Vis. 14 2008 997 1005
194. J. Shen, R. Samul, R.L. Silva, H. Akiyama, H. Liu, Y. Saishin, S.F. Hackett, S. Zinnen, K. Kossen, K. Fosnaugh, C. Vargeese, A. Gomez, K. Bouhana, R. Aitchison, P. Pavco, and P.A. Campochiaro Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1 Gene Ther. 13 3 2006 225 234
195. P.K. Kaiser, R.C. Symons, S.M. Shah, E.J. Quinlan, H. Tabandeh, D.V. Do, G. Reisen, J.A. Lockridge, B. Short, R. Guerciolini, and Q.D. Nguyen Sirna-027 Study Investigators. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027 Am. J. Ophthalmol. 150 1 2010 33 39
196. K.D. Rittenhouse, T.R. Johnson, P. Vicini, B. Hirakawa, D. Kalabat, A.H. Yang, W. Huang, and A.S. Basile RTP801 gene expression is differentially upregulated in retinopathy and is silenced by PF-04523655, a 19-Mer siRNA directed against RTP801 Invest. Ophthalmol. Vis. Sci. 55 3 2014 1232 1240
197. A. Brafman, I. Mett, M. Shafir, H. Gottlieb, G. Damari, S. Gozlan-Kelner, V. Vishnevskia-Dai, R. Skaliter, P. Einat, A. Faerman, E. Feinstein, and T. Shoshani Inhibition of oxygen-induced retinopathy in RTP801-deficient mice Invest. Ophthalmol. Vis. Sci. 45 10 2004 3796 3805
198. Q.D. Nguyen, R.A. Schachar, C.I. Nduaka, M. Sperling, A.S. Basile, K.J. Klamerus, K. Chi-Burris, E. Yan, D.A. Paggiarino, I. Rosenblatt, A. Khan, R. Aitchison, and S.S. Erlich PF-04523655 Study Group. Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients Eye (Lond.) 26 8 2012 1099 1105 (a)
199. Q.D. Nguyen, R.A. Schachar, C.I. Nduaka, M. Sperling, A.S. Basile, K.J. Klamerus, K. Chi-Burris, E. Yan, D.A. Paggiarino, I. Rosenblatt, R. Aitchison, S.S. Erlich, and DEGAS Clinical Study Group Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study) Invest. Ophthalmol. Vis. Sci. 53 12 2012 7666 7674 (b)
200. Q.D. Nguyen, R.A. Schachar, C.I. Nduaka, M. Sperling, K.J. Klamerus, K. Chi-Burris, E. Yan, D.A. Paggiarino, I. Rosenblatt, R. Aitchison, S.S. Erlich, and MONET Clinical Study Group Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study) Ophthalmology 119 9 2012 1867 1873 (c)
201. V. Sarli, and A. Giannis Targeting the kinesin spindle protein: basic principles and clinical implications Clin. Cancer Res. 14 23 2008 7583 7587
202. J. Tabernero, G.I. Shapiro, P.M. LoRusso, A. Cervantes, G.K. Schwartz, G.J. Weiss, L. Paz-Ares, D.C. Cho, J.R. Infante, M. Alsina, M.M. Gounder, R. Falzone, J. Harrop, A.C. White, I. Toudjarska, D. Bumcrot, R.E. Meyers, G. Hinkle, N. Svrzikapa, R.M. Hutabarat, V.A. Clausen, J. Cehelsky, S.V. Nochur, C. Gamba-Vitalo, A.K. Vaishnaw, D.W. Sah, J.A. Gollob, and H.A. Burris 3rd. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement Cancer Discov. 3 4 2013 406 417
203. Y. Nonaka, K. Sode, and K. Ikebukuro Screening and improvement of an anti-VEGF DNA aptamer Molecules 15 1 2010 215 225
204. Y. Nonaka, W. Yoshida, K. Abe, S. Ferri, H. Schulze, T.T. Bachmann, and K. Ikebukuro Affinity improvement of a VEGF aptamer by in silico maturation for a sensitive VEGF-detection system Anal. Chem. 85 2 2013 1132 1137
205. L.E. Benjamin, I. Hemo, and E. Keshet 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 9 1998 1591 1598
206. P. Choudhury, W. Chen, and R.C. Hunt Production of platelet-derived growth factor by interleukin-1 beta and transforming growth factor-beta-stimulated retinal pigment epithelial cells leads to contraction of collagen gels Invest. Ophthalmol. Vis. Sci. 38 5 1997 824 833
207. J. Bradley, M. Ju, and G.S. Robinson Combination therapy for the treatment of ocular neovascularization Angiogenesis 10 2 2007 141 148
208. M.A. Zarbin, and P.J. Rosenfeld Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives Retina 30 9 2010 1350 1367
209. M.S. Mulligan, E. Schmid, G.O. Till, T.E. Hugli, H.P. Friedl, R.A. Roth, and P.A. Ward C5a-dependent up-regulation in vivo of lung vascular P-selectin J. Immunol. 158 4 1997 1857 1861