Skip to main content
SpringerLink
Log in

Neovascular Age-Related Macular Degeneration

Opportunities for Development of First-in-Class Biopharmaceuticals

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Age-related macular degeneration (AMD) is a condition that may cause blindness. The prevalence of the disease in the Western world is estimated at 1–2% of the population. Over the past decade, treatment of neovascular AMD has been shifting from destruction of newly formed blood vessels towards inhibitors that silence the vascular endothelial growth factor (VEGF) pathway. Such agents are often first-in-class biopharmaceuticals that benefit from the fact that they can be locally administered in an immune-privileged environment with slow clearance. These new VEGF pathway inhibitors have improved therapeutic effects over conventional treatment and have promoted the identification of novel targets for inhibition of AMD angiogenesis. This review describes the rationale behind the shift from conventional to current treatment options and discusses investigational, most notably biopharmaceutical, drugs that are in clinical trials. It also provides possible points for improvement of these treatments, specifically regarding their delivery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Table I

Similar content being viewed by others

References

  1. de Jong PT. Age-related macular degeneration. N Engl J Med 2006; 355 (14): 1474–85

    Article  PubMed  Google Scholar 

  2. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122 (4): 564–72

    Article  PubMed  Google Scholar 

  3. Campochiaro PA, Soloway P, Ryan SJ, et al. The pathogenesis of choroidal neovascularization in patients with age-related macular degeneration. Mol Vis 1999; 5: 34

    PubMed  CAS  Google Scholar 

  4. Rodrigues EB. Inflammation in dry age-related macular degeneration. Ophthalmologica 2007; 221 (3): 143–52

    Article  PubMed  CAS  Google Scholar 

  5. Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA 2006; 296 (3): 301–9

    Article  PubMed  Google Scholar 

  6. Francis PJ, Hamon SC, Ott J, et al. Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 2009; 46 (5): 300–7

    Article  PubMed  CAS  Google Scholar 

  7. Hageman GS, Hancox LS, Taiber AJ, et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med 2006; 38 (8): 592–604

    Article  PubMed  CAS  Google Scholar 

  8. Bojanowski CM, Shen D, Chew EY, et al. An apolipoprotein E variant may protect against age-related macular degeneration through cytokine regulation. Environ Mol Mutagen 2006; 47 (8): 594–602

    Article  PubMed  CAS  Google Scholar 

  9. Malek G, Johnson LV, Mace BE, et al. Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. Proc Natl Acad Sci U S A 2005; 102 (33): 11900–5

    Article  PubMed  CAS  Google Scholar 

  10. Bourla DH, Young TA. Age-related macular degeneration: a practical approach to a challenging disease. J Am Geriatr Soc 2006; 54 (7): 1130–5

    Article  PubMed  Google Scholar 

  11. Suner IJ, Espinosa-Heidmann DG, Marin-Castano ME, et al. Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 2004; 45 (1): 311–7

    Article  PubMed  Google Scholar 

  12. Holz FG, Pauleikhoff D, Klein R, et al. Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 2004; 137 (3): 504–10

    Article  PubMed  Google Scholar 

  13. Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004; 122 (4): 477–85

    Article  PubMed  Google Scholar 

  14. Friedman DS, West SK, Munoz B, et al. Racial variations in causes of vision loss in nursing homes: the Salisbury Eye Evaluation in Nursing Home Groups (SEEING) Study. Arch Ophthalmol 2004; 122 (7): 1019–24

    Article  PubMed  Google Scholar 

  15. Lim LA, Frost NA, Powell RJ, et al. Comparison of the ETDRS logMAR, ‘compact reduced logMar’ and Snellen charts in routine clinical practice. Eye (Lond) 2009; 24 (4): 673–7

    Article  Google Scholar 

  16. Parodi MB, Virgili G, Evans JR. Laser treatment of drusen to prevent progression to advanced age-related macular degeneration. Cochrane Database Syst Rev 2009; (3): CD006537

    PubMed  Google Scholar 

  17. Helb HM, Charbel Issa P, Fleckenstein M, et al. Clinical evaluation of simultaneous confocal scanning laser ophthalmoscopy imaging combined with high-resolution, spectral-domain optical coherence tomography. Acta Ophthalmol 2010; 88 (8): 842–9

    Article  PubMed  Google Scholar 

  18. Ni Z, Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration. Ophthalmologica 2009; 223 (6): 401–10

    Article  PubMed  CAS  Google Scholar 

  19. Kulkarni AD, Kuppermann BD. Wet age-related macular degeneration. Adv Drug Deliv Rev 2005; 57 (14): 1994–2009

    Article  PubMed  CAS  Google Scholar 

  20. Bergmann M, Schutt F, Holz FG, et al. Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration. FASEB J 2004; 18 (3): 562–4

    PubMed  CAS  Google Scholar 

  21. Sparrow JR, Zhou J, Cai B. DNA is a target of the photodynamic effects elicited in A2E-laden RPE by blue-light illumination. Invest Ophthalmol Vis Sci 2003; 44 (5): 2245–51

    Article  PubMed  Google Scholar 

  22. Ramrattan RS, van der Schaft TL, Mooy CM, et al. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 1994; 35 (6): 2857–64

    PubMed  CAS  Google Scholar 

  23. Aiello LP. Clinical implications of vascular growth factors in proliferative retinopathies. Curr Opin Ophthalmol 1997; 8 (3): 19–31

    Article  PubMed  CAS  Google Scholar 

  24. Sheridan CM, Pate S, Hiscott P, et al. Expression of hypoxia-inducible factor-1alpha and -2alpha in human choroidal neovascular membranes. Graefes Arch Clin Exp Ophthalmol 2009; 247 (10): 1361–7

    Article  PubMed  CAS  Google Scholar 

  25. Zhang P, Wang Y, Hui Y, et al. Inhibition of VEGF expression by targeting HIF-1 alpha with small interference RNA in human RPE cells. Ophthalmologica 2007; 221 (6): 411–7

    Article  PubMed  CAS  Google Scholar 

  26. Schlingemann RO. Role of growth factors and the wound healing response in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2004; 242 (1): 91–101

    Article  PubMed  CAS  Google Scholar 

  27. Nagineni CN, Samuel W, Nagineni S, et al. Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol 2003; 197 (3): 453–62

    Article  PubMed  CAS  Google Scholar 

  28. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000; 55: 15–35; discussion 35-6

    PubMed  CAS  Google Scholar 

  29. Browning AC, Dua HS, Amoaku WM. The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells. Br J Ophthalmol 2008; 92 (7): 1003–8

    Article  PubMed  CAS  Google Scholar 

  30. Kliffen M, Sharma HS, Mooy CM, et al. Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol 1997; 81 (2): 154–62

    Article  PubMed  CAS  Google Scholar 

  31. Penn JS, Madan A, Caldwell RB, et al. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 2008; 27 (4): 331–71

    Article  PubMed  CAS  Google Scholar 

  32. Waisbourd M, Loewenstein A, Goldstein M, et al. Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration. Drugs Aging 2007; 24 (8): 643–62

    Article  PubMed  CAS  Google Scholar 

  33. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9 (6): 669–76

    Article  PubMed  CAS  Google Scholar 

  34. Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 2009; 29 (6): 789–91

    Article  PubMed  CAS  Google Scholar 

  35. Fischer C, Mazzone M, Jonckx B, et al. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 2008; 8 (12): 942–56

    Article  PubMed  CAS  Google Scholar 

  36. Bohlen P, Zhu Z, Hicklin DJ. Chapter 24. Vascular endothelial growth factor receptor antibodies for anti-angiogenic therapy. In: Marmé D, Fusenig N, editors. Tumor angiogenesis: basic mechanisms and cancer therapy. Berlin: Springer Verlag, 2008: 424–52

    Google Scholar 

  37. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004; 25 (4): 581–611

    Article  PubMed  CAS  Google Scholar 

  38. Lim JI, Spee C, Hangai M, et al. Neuropilin-1 expression by endothelial cells and retinal pigment epithelial cells in choroidal neovascular membranes. Am J Ophthalmol 2005; 140 (6): 1044–50

    Article  PubMed  CAS  Google Scholar 

  39. Macular Photocoagulation Study Group. Laser photocoagulation of sub-foveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 1991; 109: 1219–30

    Google Scholar 

  40. Bressler NM, Bressler SB, Hawkins BS, et al. Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes submacular surgery trials pilot study report number 1. Am J Ophthalmol 2000; 130 (4): 387–407

    Article  PubMed  CAS  Google Scholar 

  41. Schneider S, Greven CM, Green WR. Photocoagulation of well-defined choroidal neovascularization in age-related macular degeneration: clinicopathologic correlation. Retina 1998; 18 (3): 242–50

    Article  PubMed  CAS  Google Scholar 

  42. Barbazetto I, Burdan A, Bressler NM, et al. Photodynamic therapy of sub-foveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment. TAP and VIP report No. 2. Arch Ophthalmol 2003; 121 (9): 1253–68

    Article  PubMed  CAS  Google Scholar 

  43. Jonas JB. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2002; 133 (6): 857; author reply 857-9

    Article  PubMed  Google Scholar 

  44. Ghazi NG, Jabbour NM, De La Cruz ZC, et al. Clinicopathologic studies of age-related macular degeneration with classic subfoveal choroidal neovascularization treated with photodynamic therapy. Retina 2001; 21 (5): 478–86

    Article  PubMed  CAS  Google Scholar 

  45. Schmidt-Erfurth U, Hasan T. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv Ophthalmol 2000; 45 (3): 195–214

    Article  PubMed  CAS  Google Scholar 

  46. Tatar O, Adam A, Shinoda K, et al. Expression of VEGF and PEDF in choroidal neovascular membranes following verteporfin photodynamic therapy. Am J Ophthalmol 2006; 142 (1): 95–104

    Article  PubMed  CAS  Google Scholar 

  47. Tatar O, Kaiserling E, Adam A, et al. Consequences of verteporfin photodynamic therapy on choroidal neovascular membranes. Arch Ophthalmol 2006; 124 (6): 815–23

    Article  PubMed  CAS  Google Scholar 

  48. Evans JR, Sivagnanavel V, Chong V. Radiotherapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev 2010; 5: CD004004

    PubMed  Google Scholar 

  49. Avila MP, Farah ME, Santos A, et al. Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol 2009; 93 (3): 305–9

    Article  PubMed  CAS  Google Scholar 

  50. 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 (2): 157–69

    Article  PubMed  Google Scholar 

  51. Gertner M, Chell E, Pan KH, et al. Stereotactic targeting and dose verification for age-related macular degeneration. Med Phys 2010; 37 (2): 600–6

    Article  PubMed  Google Scholar 

  52. Stahl A, Paschek L, Martin G, et al. Rapamycin reduces VEGF expression in retinal pigment epithelium (RPE) and inhibits RPE-induced sprouting angiogenesis in vitro. FEBS Lett 2008; 582 (20): 3097–102

    Article  PubMed  CAS  Google Scholar 

  53. Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs 2009; 69 (16): 2227–43

    Article  PubMed  CAS  Google Scholar 

  54. Saemann MD, Haidinger M, Hecking M, et al. The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant 2009; 9 (12): 2655–61

    Article  PubMed  CAS  Google Scholar 

  55. Maeda T, Maeda A, Matosky M, et al. Evaluation of potential therapies for a mouse model of human age-related macular degeneration caused by delayed all-trans-retinal clearance. Invest Ophthalmol Vis Sci 2009; 50 (10): 4917–25

    Article  PubMed  Google Scholar 

  56. Xue Q, Hopkins B, Perruzzi C, et al. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res 2008; 68 (22): 9551–7

    Article  PubMed  CAS  Google Scholar 

  57. Yamasaki K, Asai T, Shimizu M, et al. Inhibition of NFkappaB activation using ciselement ‘decoy’ of NFkappaB binding site reduces neointimal formation in porcine balloon-injured coronary artery model. Gene Ther 2003; 10 (4): 356–64

    Article  PubMed  CAS  Google Scholar 

  58. Yokoseki O, Suzuki J, Kitabayashi H, et al. cis Element decoy against nuclear factor-kappaB attenuates development of experimental autoimmune myocarditis in rats. Circ Res 2001; 89 (10): 899–906

    Article  PubMed  CAS  Google Scholar 

  59. Tomita N, Morishita R, Tomita S, et al. Transcription factor decoy for NFkappaB inhibits TNF-alpha-induced cytokine and adhesion molecule expression in vivo. Gene Ther 2000; 7 (15): 1326–32

    Article  PubMed  CAS  Google Scholar 

  60. Li N, Chen L, Yi F, et al. Salt-sensitive hypertension induced by decoy of transcription factor hypoxia-inducible factor-1alpha in the renal medulla. Circ Res 2008; 102 (9): 1101–8

    Article  PubMed  CAS  Google Scholar 

  61. Jiang J, Bock K, Li Y, Calkins K, et al. In vivo evaluation of hypoxia-induced factor-1 (HIF-1) decoy against a panel of human tumor xenograft models [abstract no. 1530]. Proceedings of the 96th Annual Meeting of the American Association for Cancer Research; 2005 Apr 16–20; Anaheim (CA)

  62. Hadj-Slimane R, Lepelletier Y, Lopez N, et al. Short interfering RNA (siRNA), a novel therapeutic tool acting on angiogenesis. Biochimie 2007; 89 (10): 1234–44

    Article  PubMed  CAS  Google Scholar 

  63. Wouters BG, van den Beucken T, Magagnin MG, et al. Control of the hypoxic response through regulation of mRNA translation. Semin Cell Dev Biol 2005; 16 (4–5): 487–501

    PubMed  CAS  Google Scholar 

  64. Chang B, Liu G, Yang G, et al. REDD1 is required for RAS-mediated transformation of human ovarian epithelial cells. Cell Cycle 2009; 8 (5): 780–6

    Article  PubMed  CAS  Google Scholar 

  65. Wojciak JM, Zhu N, Schuerenberg KT, et al. The crystal structure of sphingosine-1-phosphate in complex with a Fab fragment reveals metal bridging of an antibody and its antigen. Proc Natl Acad Sci U S A 2009; 106 (42): 17717–22

    Article  PubMed  CAS  Google Scholar 

  66. Xie B, Shen J, Dong A, et al. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J Cell Physiol 2009; 218 (1): 192–8

    Article  PubMed  CAS  Google Scholar 

  67. Thelen U. Clinical experience with pegaptanib in the treatment of age-related macular degeneration (AMD). Klin Monbl Augenheilkd 2010; 227 (1): 67–72

    Article  PubMed  CAS  Google Scholar 

  68. Doggrell SA. Pegaptanib: the first antiangiogenic agent approved for neovascular macular degeneration. Expert Opin Pharmacother 2005; 6 (8): 1421–3

    Article  PubMed  CAS  Google Scholar 

  69. Gragoudas ES, Adamis AP, Cunningham Jr ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351 (27): 2805–16

    Article  PubMed  CAS  Google Scholar 

  70. Vinores SA. Technology evaluation: pegaptanib, Eyetech/Pfizer. Curr Opin Mol Ther 2003; 5 (6): 673–9

    PubMed  CAS  Google Scholar 

  71. 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

    Article  PubMed  CAS  Google Scholar 

  72. Chakravarthy U, Adamis AP, Cunningham Jr ET, et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology 2006; 113 (9): 1508.e1–25

    Article  CAS  Google Scholar 

  73. Gonzales CR. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis. Retina 2005; 25 (7): 815–27

    Article  PubMed  Google Scholar 

  74. D’Amico DJ, Masonson HN, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology 2006; 113 (6): 992–1001.e6

    Article  PubMed  Google Scholar 

  75. Chapman JA, Beckey C. Pegaptanib: a novel approach to ocular neovascularization. Ann Pharmacother 2006; 40 (7–8): 1322–6

    Article  PubMed  CAS  Google Scholar 

  76. Salesi N, Bossone G, Veltri E, et al. Clinical experience with bevacizumab in colorectal cancer. Anticancer Res 2005; 25 (5): 3619–23

    PubMed  CAS  Google Scholar 

  77. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005; 333 (2): 328–35

    Article  PubMed  CAS  Google Scholar 

  78. Lazic R, Gabric N. Intravitreally administered bevacizumab (Avastin) in minimally classic and occult choroidal neovascularization secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2007; 245 (1): 68–73

    Article  PubMed  CAS  Google Scholar 

  79. Geitzenauer W, Michels S, Prager F, et al. Comparison of 2.5mg/kg and 5mg/kg systemic bevacizumab in neovascular age-related macular degeneration: twenty-four week results of an uncontrolled, prospective cohort study. Retina 2008; 28 (10): 1375–86

    Article  PubMed  Google Scholar 

  80. Moshfeghi AA, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 2006; 113 (11): 2002 e1–12

    Article  Google Scholar 

  81. Zhu Q, Ziemssen F, Henke-Fahle S, et al. Vitreous levels of bevacizumab and vascular endothelial growth factor-A in patients with choroidal neovascularization. Ophthalmology 2008; 115 (10): 1750–5, 5 e1

    Article  PubMed  Google Scholar 

  82. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006; 26 (4): 383–90

    Article  PubMed  Google Scholar 

  83. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006; 26 (5): 495–511

    Article  PubMed  Google Scholar 

  84. Chan CK, Meyer CH, Gross JG, et al. Retinal pigment epithelial tears after intravitreal bevacizumab injection for neovascular age-related macular degeneration. Retina 2007; 27 (5): 541–51

    Article  PubMed  Google Scholar 

  85. Lichtlen PD, Lam T, Nork M, et al. Relative contribution of VEGF and TNF-alpha in the cynomolgus laser-induced CNV model: comparing efficacy of bevacizumab, adalimumab and ESBA105. Invest Ophthalmol Vis Sci 2010; 51 (9): 4738–45

    Article  PubMed  Google Scholar 

  86. Jyothi S, Chowdhury H, Elagouz M, et al. Intravitreal bevacizumab (Avastin) for age-related macular degeneration: a critical analysis of literature. Eye (Lond) 2010; 24 (5): 816–24

    Article  CAS  Google Scholar 

  87. Schouten JS, La Heij EC, Webers CA, et al. A systematic review on the effect of bevacizumab in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2009; 247 (1): 1–11

    Article  PubMed  CAS  Google Scholar 

  88. Blick SK, Keating GM, Wagstaff AJ. Ranibizumab. Drugs 2007; 67 (8): 1199–206; discussion 207-9

    Article  PubMed  CAS  Google Scholar 

  89. Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006; 26 (8): 859–70

    Article  PubMed  Google Scholar 

  90. Spitzer MS, Ziemssen F, Bartz-Schmidt KU, et al. Treatment of age-related macular degeneration: focus on ranibizumab. Clin Ophthalmol 2008; 2 (1): 1–14

    Article  PubMed  CAS  Google Scholar 

  91. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355 (14): 1419–31

    Article  PubMed  CAS  Google Scholar 

  92. Papadopoulou DN, Mendrinos E, Mangioris G, et al. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology 2009; 116 (9): 1755–61

    Article  PubMed  Google Scholar 

  93. 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

    Article  PubMed  CAS  Google Scholar 

  94. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. Epub 2011 Apr 28

  95. Dixon JA, Oliver SC, Olson JL, et al. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs 2009; 18 (10): 1573–80

    Article  PubMed  CAS  Google Scholar 

  96. 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 (9): 1522.e1–14

    Article  Google Scholar 

  97. Nguyen QD, Shah SM, Browning DJ, et al. A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration. Ophthalmology 2009; 116 (11): 2141–8.e1

    Article  PubMed  Google Scholar 

  98. Zhang M, Yu D, Yang C, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res 2009; 26 (1): 204–10

    Article  PubMed  CAS  Google Scholar 

  99. Zhang M, Zhang J, Yan M, et al. Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neo-vasularization in monkeys. Mol Vis 2008; 14: 37–49

    PubMed  CAS  Google Scholar 

  100. Igarashi T, Miyake K, Masuda I, et al. Adeno-associated vector (type 8)-mediated expression of soluble Flt-1 efficiently inhibits neovascularization in a murine choroidal neovascularization model. Hum Gene Ther 2010; 21 (5): 631–7

    Article  PubMed  CAS  Google Scholar 

  101. Ablonczy Z, Prakasam A, Fant J, et al. Pigment epithelium-derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor-R2 signaling through gamma-secretase. J Biol Chem 2009; 284 (44): 30177–86

    Article  PubMed  CAS  Google Scholar 

  102. Bhutto IA, McLeod DS, Hasegawa T, et al. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration. Exp Eye Res 2006; 82 (1): 99–110

    Article  PubMed  CAS  Google Scholar 

  103. Rasmussen H, Chu KW, Campochiaro P, et al. Clinical protocol: an open-label, phase I, single administration, dose-escalation study of ADGV-PEDF. 11D (ADPEDF) in neovascular age-related macular degeneration (AMD). Hum Gene Ther 2001; 12 (16): 2029–32

    PubMed  CAS  Google Scholar 

  104. Reich SJ, Fosnot J, Kuroki A, et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vis 2003; 9: 210–6

    PubMed  CAS  Google Scholar 

  105. Dejneka NS, Wan S, Bond OS, et al. Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes. Mol Vis 2008; 14: 997–1005

    PubMed  Google Scholar 

  106. Emerson MV, Lauer AK. Current and emerging therapies for the treatment of age-related macular degeneration. Clin Ophthalmol 2008; 2 (2): 377–88

    PubMed  CAS  Google Scholar 

  107. Miao HQ, Hu K, Jimenez X, et al. Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2. Biochem Biophys Res Commun 2006; 345 (1): 438–45

    Article  PubMed  CAS  Google Scholar 

  108. Ton NC, Parker GJ, Jackson A, et al. Phase I evaluation of CDP791, a PEGylated di-Fab’ conjugate that binds vascular endothelial growth factor receptor 2. Clin Cancer Res 2007; 13 (23): 7113–8

    Article  PubMed  CAS  Google Scholar 

  109. Chappelow AV, Kaiser PK. Neovascular age-related macular degeneration: potential therapies. Drugs 2008; 68 (8): 1029–36

    Article  PubMed  CAS  Google Scholar 

  110. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000; 60 (8): 2178–89

    PubMed  CAS  Google Scholar 

  111. Maier P, Unsoeld AS, Junker B, et al. Intravitreal injection of specific receptor tyrosine kinase inhibitor PTK787/ZK222 584 improves ischemia-induced retinopathy in mice. Graefes Arch Clin Exp Ophthalmol 2005; 243 (6): 593–600

    Article  PubMed  CAS  Google Scholar 

  112. Jost LM, Gschwind HP, Jalava T, et al. Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients. Drug Metab Dispos 2006; 34 (11): 1817–28

    Article  PubMed  CAS  Google Scholar 

  113. Hartman GD, Fraley ME, Bilodeau MT. Kinase insert domain-containing receptor kinase inhibitors as anti-angiogenic agents. Expert Opin Investig Drugs 2002; 11 (6): 737–45

    Article  PubMed  Google Scholar 

  114. Takahashi K, Saishin Y, King AG, et al. Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. Arch Ophthalmol 2009; 127 (4): 494–9

    Article  PubMed  CAS  Google Scholar 

  115. Shen J, Samul R, Silva RL, et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther 2006; 13 (3): 225–34

    Article  PubMed  CAS  Google Scholar 

  116. Byzova TV, Goldman CK, Pampori N, et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 2000; 6 (4): 851–60

    PubMed  CAS  Google Scholar 

  117. Stragies R, Osterkamp F, Zischinsky G, et al. Design and synthesis of a new class of selective integrin alpha5beta1 antagonists. J Med Chem 2007; 50 (16): 3786–94

    Article  PubMed  CAS  Google Scholar 

  118. Zahn G, Volk K, Lewis GP, et al. Assessment of the integrin alpha5beta1 antagonist JSM6427 in proliferative vitreoretinopathy using in vitro assays and a rabbit model of retinal detachment. Invest Ophthalmol Vis Sci 2010; 51 (2): 1028–35

    Article  PubMed  Google Scholar 

  119. Zahn G, Vossmeyer D, Stragies R, et al. Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch Ophthalmol 2009; 127 (10): 1329–35

    Article  PubMed  CAS  Google Scholar 

  120. Maier AK, Kociok N, Zahn G, et al. Modulation of hypoxia-induced neovascularization by JSM6427, an integrin alpha5beta1 inhibiting molecule. Curr Eye Res 2007; 32 (9): 801–12

    Article  PubMed  CAS  Google Scholar 

  121. Ramakrishnan V, Bhaskar V, Law DA, et al. Preclinical evaluation of an anti-alpha 5beta1 integrin antibody as a novel anti-angiogenic agent. J Exp Ther Oncol 2006; 5 (4): 273–86

    PubMed  CAS  Google Scholar 

  122. Nisato RE, Tille JC, Jonczyk A, et al. alphav beta 3 and alphav beta 5 integrin antagonists inhibit angiogenesis in vitro. Angiogenesis 2003; 6 (2): 105–19

    Article  PubMed  CAS  Google Scholar 

  123. Temming K, Schiffelers RM, Molema G, et al. RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature. Drug Resist Updat 2005; 8 (6): 381–402

    Article  PubMed  CAS  Google Scholar 

  124. Reynolds AR, Hart IR, Watson AR, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med 2009; 15 (4): 392–400

    Article  PubMed  CAS  Google Scholar 

  125. Fens MH, Storm G, Schiffelers RM. Tumor vasculature as target for therapeutic intervention. Expert Opin Investig Drugs 2010; 19 (11): 1321–38

    Article  PubMed  CAS  Google Scholar 

  126. Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis revisited. Prog Retin Eye Res 2010; 29 (2): 95–112

    Article  PubMed  CAS  Google Scholar 

  127. Parker CJ, Kar S, Kirkpatrick P. Eculizumab. Nat Rev Drug Discov 2007; 6 (7): 515–6

    Article  PubMed  CAS  Google Scholar 

  128. Nilsson B, Larsson R, Hong J, et al. Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 1998; 92 (5): 1661–7

    PubMed  CAS  Google Scholar 

  129. Markomichelakis NN, Theodossiadis PG, Sfikakis PP. Regression of neovascular age-related macular degeneration following infliximab therapy. Am J Ophthalmol 2005; 139 (3): 537–40

    Article  PubMed  Google Scholar 

  130. Theodossiadis PG, Liarakos VS, Sfikakis PP, et al. Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration. Am J Ophthalmol 2009; 147 (5): 825–30, 30.e1

    Article  PubMed  CAS  Google Scholar 

  131. Gaudana R, Jwala J, Boddu SH, et al. Recent perspectives in ocular drug delivery. Pharm Res 2009; 26 (5): 1197–216

    Article  PubMed  CAS  Google Scholar 

  132. Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 2003; 3 (11): 879–89

    Article  PubMed  CAS  Google Scholar 

  133. Meyer CH, Rodrigues EB, Michels S, et al. Incidence of damage to the crystalline lens during intravitreal injections. J Ocul Pharmacol Ther 2010; 26 (5): 491–5

    Article  PubMed  CAS  Google Scholar 

  134. Pilli S, Kotsolis A, Spaide RF, et al. Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor therapy injections in an office setting. Am J Ophthalmol 2008; 145 (5): 879–82

    Article  PubMed  CAS  Google Scholar 

  135. Meyer CH, Michels S, Rodrigues EB, et al. Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections. Acta Ophthalmol 2010; 89 (1): 70–5

    PubMed  Google Scholar 

  136. Buch PK, Bainbridge JW, Ali RR. AAV-mediated gene therapy for retinal disorders: from mouse to man. Gene Ther 2008; 15 (11): 849–57

    Article  PubMed  CAS  Google Scholar 

  137. Bennett J. Immune response following intraocular delivery of recombinant viral vectors. Gene Ther 2003; 10 (11): 977–82

    Article  PubMed  CAS  Google Scholar 

  138. Cashman SM, Bowman L, Christofferson J, et al. Inhibition of choroidal neovascularization by adenovirus-mediated delivery of short hairpin RNAs targeting VEGF as a potential therapy for AMD. Invest Ophthalmol Vis Sci 2006; 47 (8): 3496–504

    Article  PubMed  Google Scholar 

  139. Kreppel F, Luther TT, Semkova I, et al. Long-term transgene expression in the RPE after gene transfer with a high-capacity adenoviral vector. Invest Ophthalmol Vis Sci 2002; 43 (6): 1965–70

    PubMed  Google Scholar 

  140. 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): 10–6

    Article  PubMed  CAS  Google Scholar 

  141. Anand V, Barral DC, Zeng Y, et al. Gene therapy for choroideremia: in vitro rescue mediated by recombinant adenovirus. Vision Res 2003; 43 (8): 919–26

    Article  PubMed  CAS  Google Scholar 

  142. Balaggan KS, Binley K, Esapa M, et al. EIAV vector-mediated delivery of endostatin or angiostatin inhibits angiogenesis and vascular hyper-permeability in experimental CNV. Gene Ther 2006; 13 (15): 1153–65

    Article  PubMed  CAS  Google Scholar 

  143. Heller J. Drug delivery strategies to treat age-related macular degeneration. Adv Drug Deliv Rev 2005; 57 (14): 2053–62

    Article  PubMed  CAS  Google Scholar 

  144. Bourges JL, Bloquel C, Thomas A, et al. Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev 2006; 58 (11): 1182–202

    Article  PubMed  CAS  Google Scholar 

  145. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov Today 2008; 13 (3–4): 135–43

    Google Scholar 

  146. Bourges JL, Gautier SE, Delie F, et al. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci 2003; 44 (8): 3562–9

    Article  PubMed  Google Scholar 

  147. Saishin Y, Silva RL, Callahan K, et al. Periocular injection of microspheres containing PKC412 inhibits choroidal neovascularization in a porcine model. Invest Ophthalmol Vis Sci 2003; 44 (11): 4989–93

    Article  PubMed  Google Scholar 

  148. Carrasquillo KG, Ricker JA, Rigas IK, et al. Controlled delivery of the anti-VEGF aptamer EYE001 with poly (lactic-co-glycolic)acid microspheres. Invest Ophthalmol Vis Sci 2003; 44 (1): 290–9

    Article  PubMed  Google Scholar 

  149. Fattal E, Bochot A. Ocular delivery of nucleic acids: antisense oligonucleotides, aptamers and siRNA. Adv Drug Deliv Rev 2006; 58 (11): 1203–23

    Article  PubMed  CAS  Google Scholar 

  150. Gomes dos Santos AL, Bochot A, Doyle A, et al. Sustained release of nanosized complexes of polyethylenimine and anti-TGF-beta 2 oligonucleotide improves the outcome of glaucoma surgery. J Control Release 2006; 112 (3): 369–81

    Article  CAS  Google Scholar 

  151. Gomes dos Santos AL, Bochot A, Tsapis N, et al. Oligonucleotide-polyethylenimine complexes targeting retinal cells: structural analysis and application to anti-TGFbeta-2 therapy. Pharm Res 2006; 23 (4): 770–81

    Article  CAS  Google Scholar 

  152. Marano RJ, Toth I, Wimmer N, et al. Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity. Gene Ther 2005; 12 (21): 1544–50

    Article  PubMed  CAS  Google Scholar 

  153. Camelo S, Lajavardi L, Bochot A, et al. Ocular and systemic bio-distribution of rhodamine-conjugated liposomes loaded with VIP injected into the vitreous of Lewis rats. Mol Vis 2007; 13: 2263–74

    PubMed  CAS  Google Scholar 

  154. Abrishami M, Ganavati SZ, Soroush D, et al. Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 2009; 29 (5): 699–703

    Article  PubMed  Google Scholar 

  155. Inokuchi Y, Hironaka K, Fujisawa T, et al. Physicochemical properties affecting retinal drug/coumarin-6 delivery from nanocarrier systems via eye-drop administration. Invest Ophthalmol Vis Sci 2010; 51 (6): 3162–70

    Article  PubMed  Google Scholar 

  156. Hironaka K, Inokuchi Y, Tozuka Y, et al. Design and evaluation of a liposomal delivery system targeting the posterior segment of the eye. J Control Release 2009; 136 (3): 247–53

    Article  PubMed  CAS  Google Scholar 

  157. Zhou XY, Liao Q, Pu YM, et al. Ultrasound-mediated microbubble delivery of pigment epithelium-derived factor gene into retina inhibits choroidal neovascularization. Chin Med J (Engl) 2009; 122 (22): 2711–7

    CAS  Google Scholar 

  158. Myles ME, Neumann DM, Hill JM. Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis. Adv Drug Deliv Rev 2005; 57 (14): 2063–79

    Article  PubMed  CAS  Google Scholar 

  159. Berdugo M, Valamanesh F, Andrieu C, et al. Delivery of antisense oligonu-cleotide to the cornea by iontophoresis. Antisense Nucleic Acid Drug Dev 2003; 13 (2): 107–14

    Article  PubMed  CAS  Google Scholar 

  160. Parkinson TM, Ferguson E, Febbraro S, et al. Tolerance of ocular iontophoresis in healthy volunteers. J Ocul Pharmacol Ther 2003; 19 (2): 145–51

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No funding has been received for the preparation of this manuscript. The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Sorbonnelaan 16, 3584 CA, Utrecht, the Netherlands

    Raymond M. Schiffelers, Tjitske K. van der Vaart & Gert Storm

Authors
  1. Raymond M. Schiffelers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tjitske K. van der Vaart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gert Storm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raymond M. Schiffelers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schiffelers, R.M., van der Vaart, T.K. & Storm, G. Neovascular Age-Related Macular Degeneration. BioDrugs 25, 171–189 (2011). https://doi.org/10.2165/11589330-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11589330-000000000-00000

Keywords

Search

Navigation