Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease

Nature Reviews Drug Discovery volume 5, pages 123–132 (2006)Cite this article

Key Points

  • Aptamers are RNA or DNA oligonucleotides that are selected through systematic evolution to bind to proteins with both affinity and specificity.

  • Aptamers offer the specificity and affinity advantages of antibodies in a relatively small, chemically synthesized molecule free from cell-culture-derived contaminants. They are also essentially non-immunogenic.

  • In contrast to other oligonucleotide agents, such as antisense oligonucleotides, aptamers can act on extracellular targets.

  • Vascular endothelial growth factor (VEGF) was selected as a target for aptamer development owing to its key role in pathological angiogenesis, for example, in ocular neovascular diseases such as age-related macular degeneration (AMD) and diabetic macular oedema.

  • After the selection of anti-VEGF aptamers that blocked the actions of VEGF in vitro, further optimization of the pharmacokinetic properties, for example by using 2′-F substitutions, resulted in the pegylated aptamer pegaptanib, which was chosen for clinical development.

  • Pegaptanib, administered by intravitreous injection, was tested in clinical trials in patients with neovascular AMD, and on the basis of its ability to reduce vision loss, was approved by the US FDA in December 2004.

Abstract

Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability. After nearly a decade of preclinical development to optimize and characterize its biological effects, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Pegaptanib therefore has the notable distinction of being the first aptamer therapeutic approved for use in humans, paving the way for future aptamer applications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A depiction of the SELEX process7.
Figure 2: Pegaptanib structure and target binding.
Figure 3: Mean visual acuity throughout 2 years.

Similar content being viewed by others

References

  1. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Rev. Drug Discov. 3, 391–400 (2004). This review provides a comprehensive overview of VEGF and its role in angiogenesis.

    Article  CAS  Google Scholar 

  2. Kitajewski, J. et al. Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 α kinase. Cell 45, 195–200 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, J. et al. HIV-1 TAR RNA enhances the interaction between Tat and cyclin T1. J. Biol. Chem. 275, 34314–34319 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Ellington, A. D. & Szostak, J. W. In vitro selection of RNA molecules that bind specific ligands. Nature 346, 818–822 (1990).

    Article  CAS  Google Scholar 

  5. Buerger, C. & Groner, B. Bifunctional recombinant proteins in cancer therapy: cell penetrating peptide aptamers as inhibitors of growth factor signaling. J. Cancer Res. Clin. Oncol. 129, 669–675 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Crawford, M., Woodman, R. & Ko Ferrigno, P. Peptide aptamers: tools for biology and drug discovery. Brief. Funct. Genomic. Proteomic. 2, 72–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Eaton, B. The joys of in vitro selection: chemically dressing oligonucleotides to satiate protein targets. Curr. Opin. Chem. Biol. 1, 10–16 (2005).

    Article  Google Scholar 

  8. Tuerk, C. & Gold, L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249, 505–510 (1990). These investigators were the first to describe the use of SELEX technology in developing targeted aptamers.

    Article  CAS  PubMed  Google Scholar 

  9. Jayasena, S. D. Aptamers: an emerging class of molecules that rival antibodies in diagnostics. Clin. Chem. 45, 1628–1650 (1999).

    CAS  PubMed  Google Scholar 

  10. de Smidt, P. C., Le Doan, T., de Falco, S. & van Berkel, T. J. Association of antisense oligonucleotides with lipoproteins prolongs the plasma half-life and modifies the tissue distribution. Nucleic Acids Res. 19, 4695–4700 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Griffin, L. C., Tidmarsh, G. F., Bock, L. C., Toole, J. J. & Leung, L. L. In vivo anticoagulant properties of a novel nucleotide-based thrombin inhibitor and demonstration of regional anticoagulation in extracorporeal circuits. Blood 81, 3271–3276 (1993).

    CAS  PubMed  Google Scholar 

  12. Pieken, W. A., Olsen, D. B., Benseler, F., Aurup, H. & Eckstein, F. Kinetic characterization of ribonuclease-resistant 2′-modified hammerhead ribozymes. Science 253, 314–317 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Green, L. S. et al. Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor. Chem. Biol. 2, 683–695 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Ruckman, J. et al. 2′-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF 165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. J. Biol. Chem. 273, 20556–20567 (1998). These studies performed extensive in vitro characterization of three candidate aptamers, one of which ultimately was developed as pegaptanib.

    Article  CAS  PubMed  Google Scholar 

  15. Burmeister, P. E. et al. Direct in vitro selection of a 2′-O-methyl aptamer to VEGF. Chem. Biol. 12, 25–33 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Rimmele, M. Nucleic acid aptamers as tools and drugs: recent developments. Chembiochem. 4, 963–971 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Nimjee, S. M., Rusconi, C. P. & Sullenger, B. A. Aptamers: an emerging class of therapeutics. Annu. Rev. Med. 56, 555–583 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Mayor, G., Grattinger, M. & Blind, M. Aptamers: multifunctional tools for target validation and drug discovery. DrugPlus International Nov /Dec (2003).

    Google Scholar 

  19. Ulrich, H., Martins, A. H. & Pesquero, J. B. RNA and DNA aptamers in cytomics analysis. Cytometry A 59, 220–231 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Blind, M., Kolanus, W. & Famulok, M. Cytoplasmic RNA modulators of an inside-out signal-transduction cascade. Proc. Natl Acad. Sci. USA 96, 3606–3610 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Famulok, M., Blind, M. & Mayer, G. Intramers as promising new tools in functional proteomics. Chem. Biol. 8, 931–939 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Doudna, J. A., Cech, T. R. & Sullenger, B. A. Selection of an RNA molecule that mimics a major autoantigenic epitope of human insulin receptor. Proc. Natl Acad. Sci. USA 92, 2355–2359 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Michaud, M. et al. A DNA aptamer as a new target-specific chiral selector for HPLC. J. Am. Chem. Soc. 125, 8672–8679 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Hermann, T. & Patel, D. J. Adaptive recognition by nucleic acid aptamers. Science 287, 820–825 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Breaker, R. R. Natural and engineered nucleic acids as tools to explore biology. Nature 432, 838–845 (2004).

    Article  CAS  Google Scholar 

  26. Peracchi, A. Prospects for antiviral ribozymes and deoxyribozymes. Rev. Med. Virol. 14, 47–64 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Hendry, P., McCall, M. J., Stewart, T. S. & Lockett, T. J. Redesigned and chemically-modified hammerhead ribozymes with improved activity and serum stability. BMC Chem. Biol. 4, 1 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jason, T. L., Koropatnick, J., Berg, R. W. Toxicology of antisense therapeutics. Toxicol. Appl. Pharmacol. 201, 66–83 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. White, R. R., Sullenger, B. A. & Rusconi, C. P. Developing aptamers into therapeutics. J. Clin. Invest. 106, 929–934 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wlotzka, B. et al. In vivo properties of an anti-GnRH Spiegelmer: an example of an oligonucleotide-based therapeutic substance class. Proc. Natl Acad. Sci. USA 99, 8898–8902 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Miele, E., Markowitz, J. E., Mamula, P. & Baldassano, R. N. Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab. J. Pediatr. Gastroenterol. Nutr. 38, 502–508 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Richards, J. et al. Phase I evaluation of humanized OKT3: toxicity and immunomodulatory effects of hOKT3gamma4. Cancer Res. 59, 2096–2101 (1999).

    CAS  PubMed  Google Scholar 

  33. Jellinek, D., Green, L. S., Bell, C. & Janjic, N. Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth factor. Biochemistry 33, 10450–10456 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  35. Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983–985 (1983).

    Article  CAS  PubMed  Google Scholar 

  36. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306–1309 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Keck, P. J. et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246, 1309–1312 (1989).

    Article  CAS  PubMed  Google Scholar 

  38. Aurup, H., Tuschl, T., Benseler, F., Ludwig, J. & Eckstein, F. Oligonucleotide duplexes containing 2′-amino-2′-deoxycytidines: thermal stability and chemical reactivity. Nucleic Acids Res. 22, 20–24 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lesnik, E. A. et al. Oligodeoxynucleotides containing 2′-O-modified adenosine: synthesis and effects on stability of DNA:RNA duplexes. Biochemistry 32, 7832–7838 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Cummins, L. L. et al. Characterization of fully 2′-modified oligoribonucleotide hetero- and homoduplex hybridization and nuclease sensitivity. Nucleic Acids Res. 23, 2019–2024 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Eaton, B. E., Gold, L. & Zichi, D. A. Let's get specific: the relationship between specificity and affinity. Chem. Biol. 346, 818–822 (1995).

    Google Scholar 

  42. Healy, J. M. et al. Pharmacokinetics and biodistribution of novel aptamer compositions. Pharm. Res. 21, 2234–2246 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Bell, C., Lynam, E., Landfair, D. J., Janjic, N. & Wiles, M. E. Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro. In Vitro Cell. Dev. Biol. Anim. 35, 533–542 (1999). Studies established the abilities of pegaptanib to block binding of VEGF to receptors on endothelial cells and to interfere with VEGF-mediated signal transduction.

    Article  CAS  PubMed  Google Scholar 

  44. 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, 143–152 (2002).

  45. Fairbrother, W. J., Champe, M. A., Christinger, H. W., Keyt, B. A. & Starovasnik, M. A. Solution structure of the heparin-binding domain of vascular endothelial growth factor. Structure 6, 637–648 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, J.-H. et al. A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165 . Proc. Natl Acad. Sci. USA [epub ahead of print].

  47. Tucker, C. E. et al. Detection and plasma pharmacokinetics of an anti-vascular endothelial growth factor oligonucleotide-aptamer (NX1838) in rhesus monkeys. J. Chromatogr. B. Biomed. Sci. Appl. 732, 203–212 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Drolet, D. W. et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm. Res. 17, 1503–1510 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Asahara, T. et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 18, 3964–3972 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Csaky, K. G. et al. Recruitment of marrow-derived endothelial cells to experimental choroidal neovascularization by local expression of vascular endothelial growth factor. Exp. Eye. Res. 78, 1107–1116 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Alon, T. et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat. Med. 1, 1024–1028 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A., Hasty, K. A. & Charles, S. T. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc. Res. 55, 29–42 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Miyamoto, K. et al. Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am. J. Pathol. 156, 1733–1739 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ishida, S. et al. VEGF164 is proinflammatory in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 44, 2155–2162 (2003).

    Article  PubMed  Google Scholar 

  55. Antonetti, D. A., Barber, A. J., Hollinger, L. A., Wolpert, E. B. & Gardner, T. W. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J. Biol. Chem. 274, 23463–23467 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Roberts, W. G. & Palade, G. E. Neovasculature induced by vascular endothelial growth factor is fenestrated. Cancer Res. 57, 765–772 (1997).

    CAS  PubMed  Google Scholar 

  57. Storkebaum, E. & Carmeliet, P. VEGF: a critical player in neurodegeneration. J. Clin. Invest. 113, 14–18 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jin, K. L., Mao, X. O. & Greenberg, D. A. Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal. J. Mol. Neurosci. 14, 197–203 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Shima, D. T., Nishijima, K., Jo, N. & Adamis, A. P. VEGF-mediated neuroprotection in ischemic retina. Invest. Ophthalmol. Vis. Sci. 45, E-abstract 3270 (2004).

    Google Scholar 

  60. Aiello, L. P. et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331, 1480–1487 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Adamis, A. P. et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118, 445–450 (1994).

    Article  CAS  PubMed  Google Scholar 

  62. Frank, R. N., Amin, R. H., Eliott, D., Puklin, J. E. & Abrams, G. W. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am. J. Ophthalmol. 122, 393–403 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Tolentino, M. J. et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch. Ophthalmol. 114, 964–970 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Tolentino, M. J. et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 103, 1820–1828 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Tolentino, M. J. et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am. J. Ophthalmol. 133, 373–385 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Baffi, J., Byrnes, G., Chan, C. C. & Csaky, K. G. Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. Invest. Ophthalmol. Vis. Sci. 41, 3582–3589 (2000).

    CAS  PubMed  Google Scholar 

  67. Spilsbury, K., Garrett, K. L., Shen, W. Y., Constable, I. J. & Rakoczy, P. E. Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am. J. Pathol. 157, 135–144 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ohno-Matsui, K. et al. Inducible expression of vascular endothelial growth factor in adult mice causes severe proliferative retinopathy and retinal detachment. Am. J. Pathol. 160, 711–719 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Aiello, L. P. et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl Acad. Sci. USA 92, 10457–10461 (1995).

    Article  CAS  PubMed  Google Scholar 

  70. Adamis, A. P. et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch. Ophthalmol. 114, 66–71 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Krzystolik, M. G. et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthalmol. 120, 338–346 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Amano, S., Rohan, R., Kuroki, M., Tolentino, M. & Adamis, A. P. Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 39, 18–22 (1998).

    CAS  PubMed  Google Scholar 

  73. Usui, T. et al. VEGF 164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2. Invest. Ophthalmol. Vis. Sci. 45, 368–374 (2004).

    Article  PubMed  Google Scholar 

  74. Ishida, S. et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J. Exp. Med. 198, 483–489 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Resnikoff, S. et al. Global data on visual impairment in the year 2002. Bull. World Health Organ. 82, 844–851 (2004).

    PubMed  PubMed Central  Google Scholar 

  76. Ambati, J., Ambati, B. K., Yoo, S. H., Ianchulev, S. & Adamis, A. P. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv. Ophthalmol. 48, 257–293 (2003).

    Article  PubMed  Google Scholar 

  77. Gragoudas, E. S., Adamis, A. P., Cunningham, E. T. Jr., Feinsod, M. & Guyer, D. R. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351, 2805–2816 (2004). Two concurrent, prospective, randomized, double-blind, multicentre, dose-ranging, controlled clinical trials using broad entry criteria demonstrated efficacy and safety in patients with age-related macular degeneration.

    Article  CAS  PubMed  Google Scholar 

  78. D'Amico, D. J. & VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group. VEGF inhibition study in ocular neovascularization (VISION): Second year efficacy data. Invest. Ophthalmol. Vis. Sci. 46, E-abstract 2309 (2005).

    Google Scholar 

  79. Ng, E. W. & Adamis, A. P. Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can. J. Ophthalmol. 40, 352–368 (2005).

    Article  PubMed  Google Scholar 

  80. D'Amico, D. J. et al. Pegaptanib sodium, an anti-VEGF aptamer, for neovascular age-related macular degeneration: safety results of the 2 prospective, multicenter, controlled trials. Ophthalmology (in the press).

  81. Gonzales, C. R. et al. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis. Retina. 25, 815–827 (2005).

    Article  PubMed  Google Scholar 

  82. Ciulla, T. A., Amador, A. G. & Zinman, B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care 26, 2653–2664 (2003).

    Article  PubMed  Google Scholar 

  83. Qaum, T. et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest. Ophthalmol. Vis. Sci. 42, 2408–2413 (2001).

    CAS  PubMed  Google Scholar 

  84. Cunningham, E. T. Jr et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 112, 1747–1757 (2005). A multicentre, Phase II trial of patients with diabetic macular oedema demonstrated efficacy across a spectrum of patients.

    Article  PubMed  Google Scholar 

  85. Jager, R. D., Aiello, L. P., Patel, S. C. & Cunningham, E. T. Jr. Risks of intravitreous injection: a comprehensive review. Retina 24, 676–698 (2004).

    Article  PubMed  Google Scholar 

  86. Peyman, G. A. & Ganiban, G. J. Delivery systems for intraocular routes. Adv. Drug Del. Rev. 16, 107 (1995).

    Article  CAS  Google Scholar 

  87. Schwendeman, S., Costantino, H., Gupta, R. & Langer, R. In Controlled Drug Delivery: Challenges and Strategies (ed. Park, K.) 229–268 (American Chemical Society, Washington, DC, 1997).

    Google Scholar 

  88. Carrasquillo, K. G. et al. Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic) acid microspheres. Invest. Ophthalmol. Vis. Sci. 44, 290–299 (2003).

    Article  PubMed  Google Scholar 

  89. Ambati, J. et al. Diffusion of high molecular weight compounds through sclera. Invest. Ophthalmol. Vis. Sci. 41, 1181–1185 (2000).

    CAS  PubMed  Google Scholar 

  90. Ambati, J. et al. Transscleral delivery of bioactive protein to the choroid and retina. Invest. Ophthalmol. Vis. Sci. 41, 1186–1191 (2000).

    CAS  PubMed  Google Scholar 

  91. Shuler, R. K. Jr. et al. Scleral permeability of a small, single-stranded oligonucleotide. J. Ocul. Pharmacol. Ther. 20, 159–168 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Eulberg, D. & Klussmann, S. Spiegelmers: biostable aptamers. Chembiochem. 4, 979–983 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Song, S., Ewald, A. J., Stallcup, W., Werb, Z. & Bergers, G. PDGFRβ(+) perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nature Cell Biol. 7, 870–879 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Green, L. S. et al. Inhibitory DNA ligands to platelet-derived growth factor B-chain. Biochemistry 35, 14413–14424 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Ostendorf, T. et al. Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J. Am. Soc. Nephrol. 12, 909–918 (2001).

    CAS  PubMed  Google Scholar 

  97. Balasubramaniam, V. et al. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L826–833 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Rusconi, C. P. et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nature Biotechnol. 22, 1423–1428 (2004).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Eyetech Pharmaceuticals, Inc., 3 Times Square, 12th Floor, New York, 10036, New York, USA

    Eugene W. M. Ng, David T. Shima, Perry Calias, Emmett T. Cunningham Jr., David R. Guyer & Anthony P. Adamis

Authors
  1. Eugene W. M. Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David T. Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Perry Calias
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmett T. Cunningham Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David R. Guyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anthony P. Adamis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anthony P. Adamis.

Ethics declarations

Competing interests

The authors are employees and shareholders of Eyetech Pharmaceuticals.

Related links

Related links

DATABASES

OMIM

Rheumatoid arthritis

FURTHER INFORMATION

American Society of Clinical Oncology

Antisoma website

Archemix website

National Eye Institute website

Visudyne prescribing information

Glossary

Age-related macular degeneration

A disease process characterized by deterioration of the macula that results in a loss of sharp central vision; non-exudative ('dry') and exudative ('wet') forms occur.

Diabetic macular oedema

Thickening of the retina occurring as a result of an abnormal accumulation of fluid within the retina; a common complication of diabetes mellitus.

Intravitreous injection

Injection of medication, air or gas into the vitreous cavity.

Vitreous

A thick, transparent, colourless, gelatinous fluid that fills the posterior segment of the eye; also known as the vitreous humour.

Retinal pigment epithelium

A layer of highly pigmented, phagocytic epithelial cells underlying the photoreceptors of the eye; it is a selective barrier controlling the flow of nutrients and other compounds to the retina.

Ocular neovascularization

A pathological condition involving the proliferation of new blood vessels in any ocular tissue.

Choroidal neovascularization

A pathological condition involving the proliferation of new blood vessels within the choroid (the vascular layer underlying the retina).

Macula

The pigmented central area of the retina adjacent to the optic nerve that contains the fovea, a region of highly concentrated photoreceptor cells important for visualizing fine detail.

Photocoagulation

A therapy in which a light wave energy (from a laser or other light source) is used directly to coagulate (cauterize) leaky or proliferating ocular vasculature.

Photodynamic therapy

A therapy in which laser energy is used to activate a photosensitive compound (administered intravenously), inducing local formation of free radicals and other compounds that cause coagulation of proliferating ocular vasculature.

Visual acuity

A quantitative measure of optical acuity based on an assessment of one's ability to see a clearly focused image at a defined distance.

Retinal detachment

Separation of sensory retina from the underlying retinal pigment epithelium; can result from subretinal fluid accumulation, retinal tear or retinal disease processes.

Endophthalmitis

Inflammation of the internal structure of the eye; in most cases the inflammation occurs as a result of infection.

Retinopathy

Any non-inflammatory disease of the retina; commonly describes a retinal degenerative condition resulting from impaired ocular circulation, hypoxia or systemic disease.

Sclera

The tough, fibrous, white outer coat of the eye; it is continuous with the cornea and the external sheath of the optic nerve.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ng, E., Shima, D., Calias, P. et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5, 123–132 (2006). https://doi.org/10.1038/nrd1955

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1955

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing