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Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma

This article has been updated

Key Points

  • Blindness affects millions of people worldwide. The leading causes of irreversible visual impairment include age-related macular degeneration (AMD), retinal vascular diseases and glaucoma.

  • During the past decade there have been substantial advances in our understanding of the pathogenesis and genetics of ophthalmic diseases, and the extent of treatable conditions and treatment options continues to increase.

  • Intravitreal injection of anti-angiogenic agents has emerged as the most effective therapy for AMD and retinal vascular diseases. Clinical trials are underway to evaluate new drugs directed against several novel targets in the complement system and angiogenic pathways for the treatment of AMD, and neuroprotective drugs are being investigated for the treatment of both AMD and glaucoma. Other promising therapeutics include gene therapy and stem cell therapy.

  • However, there are still no effective therapies for several common disorders that cause blindness, and many individuals with glaucoma develop progressive loss of vision despite receiving treatment with intraocular pressure-lowering drugs. Moreover, intraocular injection is not an ideal drug delivery platform despite the overall efficacy of anti-VEGF (vascular endothelial growth factor) therapies.

  • Present research is aimed at improving our understanding of pathogenic processes, identification of potential therapeutic targets and optimization of ocular drug delivery by utilizing novel strategies such as encapsulated cell technology and applications of nanomedicine.

  • Recent scientific developments have presented new opportunities to make major advances in ophthalmology, and a vigorous effort to develop new therapies is currently underway.

Abstract

Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.

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Figure 1: Human eye structure and diseases.
Figure 2: Retinal anatomy and structure in health and diseases.
Figure 3: Proposed pathophysiology of AMD, and locations in the pathway in which different therapeutic interventions might be effective.
Figure 4: Mechanism of action of ocular angiogenesis inhibitors in clinical care or development.
Figure 5: Agents that lower intraocular pressure.
Figure 6: Complement pathways, their association with AMD and drug targets.

Change history

  • 22 June 2012

    The second address affiliation has been updated to include the Shiley Eye Center.

References

  1. Rein, D. B. et al. The economic burden of major adult visual disorders in the United States. Arch. Ophthalmol. 124, 1754–1760 (2006).

    Article  PubMed  Google Scholar 

  2. Gaudana, R., Ananthula, H. K., Parenky, A. & Mitra, A. K. Ocular drug delivery. AAPS J. 12, 348–360 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jager, R. D., Mieler, W. F. & Miller, J. W. Age-related macular degeneration. N. Engl. J. Med. 358, 2606–2617 (2008). This paper provides a general overview of AMD.

    Article  CAS  PubMed  Google Scholar 

  4. Zarbin, M. A. & Rosenfeld, P. J. Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 30, 1350–1367 (2010). This is a review on the molecular pathways that are involved in AMD as well as targets for drug development.

    Article  PubMed  Google Scholar 

  5. Yehoshua, Z., Rosenfeld, P. J. & Albini, T. A. Current clinical trials in dry AMD and the definition of appropriate clinical outcome measures. Semin. Ophthalmol. 26, 167–180 (2011).

    Article  PubMed  Google Scholar 

  6. Weinreb, R. N. & Khaw, P. T. Primary open-angle glaucoma. Lancet 363, 1711–1720 (2004). This is a general overview of primary open-angle glaucoma.

    Article  PubMed  Google Scholar 

  7. Haddad, S., Chen, C. A., Santangelo, S. L. & Seddon, J. M. The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 51, 316–363 (2006).

    Article  PubMed  Google Scholar 

  8. Rattner, A. & Nathans, J. Macular degeneration: recent advances and therapeutic opportunities. Nature Rev. Neurosci. 7, 860–872 (2006).

    Article  CAS  Google Scholar 

  9. Penfold, P. L., Killingsworth, M. C. & Sarks, S. H. Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch. Clin. Exp. Ophthalmol. 223, 69–76 (1985).

    Article  CAS  PubMed  Google Scholar 

  10. Klein, R., Klein, B. E. & Linton, K. L. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 99, 933–943 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Vingerling, J. R. et al. The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 102, 205–210 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Hageman, G. S. et al. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog. Retin. Eye Res. 20, 705–732 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Kaplan, H. J., Leibole, M. A., Tezel, T. & Ferguson, T. A. Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Nature Med. 5, 292–297 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. 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 

  15. Okamoto, N. et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am. J. Pathol. 151, 281–291 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Friedman, D. S. et al. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol. 122, 564–572 (2004).

    Article  PubMed  Google Scholar 

  17. Dithmar, S. et al. Murine high-fat diet and laser photochemical model of basal deposits in Bruch membrane. Arch. Ophthalmol. 119, 1643–1649 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Green, W. R. & Key, S. N. Senile macular degeneration: a histopathologic study. Trans. Am. Ophthalmol. Soc. 75, 180–254 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hageman, G. S. & Mullins, R. F. Molecular composition of drusen as related to substructural phenotype. Mol. Vis. 5, 28 (1999).

    CAS  PubMed  Google Scholar 

  20. Kvanta, A., Algvere, P. V., Berglin, L. & Seregard, S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest. Ophthalmol. Vis. Sci. 37, 1929–1934 (1996).

    CAS  PubMed  Google Scholar 

  21. Hageman, G. S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl Acad. Sci. USA 102, 7227–7232 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mullins, R. F., Russell, S. R., Anderson, D. H. & Hageman, G. S. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 14, 835–846 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Mullins, R. F., Aptsiauri, N. & Hageman, G. S. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 15, 390–395 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Anderson, R. E. et al. Low docosahexaenoic acid levels in rod outer segments of rats with P23H and S334ter rhodopsin mutations. Mol. Vis. 8, 351–358 (2002).

    CAS  PubMed  Google Scholar 

  25. Johnson, L. V., Leitner, W. P., Staples, M. K. & Anderson, D. H. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp. Eye Res. 73, 887–896 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Crabb, J. W. et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc. Natl Acad. Sci. USA 99, 14682–14687 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang, Z. et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314, 992–993 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Gehrs, K. M., Anderson, D. H., Johnson, L. V. & Hageman, G. S. Age-related macular degeneration — emerging pathogenetic and therapeutic concepts. Ann. Med. 38, 450–471 (2006).

    Article  PubMed  Google Scholar 

  29. Kaneko, H. et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471, 325–330 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weismann, D. et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478, 76–81 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nozaki, M. et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc. Natl Acad. Sci. USA 103, 2328–2333 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ferrara, N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nature Med. 16, 1107–1111 (2010). This is a good review on the biology of VEGF and the use of anti-VEGF therapy in AMD.

    Article  CAS  PubMed  Google Scholar 

  33. 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 

  34. 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 

  35. Hollyfield, J. G. et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nature Med. 14, 194–198 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Tuo, J. et al. Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 48, 3827–3836 (2007).

    Article  PubMed  Google Scholar 

  37. Karan, G. et al. Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proc. Natl Acad. Sci. USA 102, 4164–4169 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maeda, A., Maeda, T., Golczak, M. & Palczewski, K. Retinopathy in mice induced by disrupted all-trans-retinal clearance. J. Biol. Chem. 283, 26684–26693 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang, Z. et al. Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J. Clin. Invest. 118, 2908–2916 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jones, A. et al. Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc. Natl Acad. Sci. USA 108, 14578–14583 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch. Ophthalmol. 119, 1417–1436 (2001).

  42. Varma, R. et al. Biologic risk factors associated with diabetic retinopathy: the Los Angeles Latino Eye Study. Ophthalmology 114, 1332–1340 (2007).

    Article  PubMed  Google Scholar 

  43. Patel, S., Chen, H., Tinkham, N. H. & Zhang, K. Genetic susceptibility of diabetic retinopathy. Curr. Diab. Rep. 8, 257–262 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Yucel, Y. H., Zhang, Q., Weinreb, R. N., Kaufman, P. L. & Gupta, N. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog. Retin. Eye Res. 22, 465–481 (2003).

    Article  PubMed  Google Scholar 

  45. Quigley, H. A. Glaucoma. Lancet 377, 1367–1377 (2011).

    Article  PubMed  Google Scholar 

  46. 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 

  47. Weinreb, R. N. & Harris, A. (eds) Ocular Blood Flow in Glaucoma (Kugler Publications Amsterdam, 2009).

    Google Scholar 

  48. Weinreb, R. N. et al. Risk assessment in the management of patients with ocular hypertension. Am. J. Ophthalmol. 138, 458–467 (2004).

    Article  PubMed  Google Scholar 

  49. Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1432–1444 (2006). This was one of the first reports to demonstrate the efficacy of anti-VEGF antibody therapy in exudative AMD.

    Article  CAS  PubMed  Google Scholar 

  50. Rosenfeld, P. J. et al. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1419–1431 (2006). This was one of the first reports to demonstrate the efficacy of anti-VEGF antibody therapy in exudative AMD.

    Article  CAS  PubMed  Google Scholar 

  51. Martin, D. F. et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 364, 1897–1908 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Rich, R. M. et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 26, 495–511 (2006).

    Article  PubMed  Google Scholar 

  53. Shih, T. Y., Gaydos, C. A., Rothman, R. E. & Hsieh, Y. H. Poor provider adherence to the Centers for Disease Control and Prevention treatment guidelines in US emergency department visits with a diagnosis of pelvic inflammatory disease. Sex Transm. Dis. 38, 299–305 (2011).

    Article  PubMed  Google Scholar 

  54. Zhang, M. et al. A Phase 1 study of KH902, a vascular endothelial growth factor receptor decoy, for exudative age-related macular degeneration. Ophthalmology 118, 672–678 (2011).

    Article  PubMed  Google Scholar 

  55. Nguyen, Q. D. 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 113, 1522.e1–1522.e14 (2006).

    Article  Google Scholar 

  56. Brown, D. M. et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a Phase III study. Ophthalmology 117, 1124–1133 (2010).

    Article  PubMed  Google Scholar 

  57. Elman, M. J. et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 117, 1064–1077 (2010).

    Article  PubMed  Google Scholar 

  58. Elman, M. J. et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 118, 609–614 (2011).

    Article  PubMed  Google Scholar 

  59. Migdal, C. Glaucoma medical treatment: philosophy, principles and practice. Eye 14, 515–518 (2000).

    Article  PubMed  Google Scholar 

  60. Medeiros, F. A. & Weinreb, R. N. Medical backgrounders: glaucoma. Drugs Today 38, 563–570 (2002).

    Article  Google Scholar 

  61. Sagara, T. et al. Topical prostaglandin F2alpha treatment reduces collagen types I, III, and IV in the monkey uveoscleral outflow pathway. Arch. Ophthalmol. 117, 794–801 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Liu, J. H., Kripke, D. F. & Weinreb, R. N. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am. J. Ophthalmol. 138, 389–395 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Nathanson, J. A. Human ciliary process adrenergic receptor: pharmacological characterization. Invest. Ophthalmol. Vis. Sci. 21, 798–804 (1981).

    CAS  PubMed  Google Scholar 

  64. Liu, J. H., Medeiros, F. A., Slight, J. R. & Weinreb, R. N. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy. Ophthalmology 116, 449–454 (2009).

    Article  PubMed  Google Scholar 

  65. Liu, J. H., Medeiros, F. A., Slight, J. R. & Weinreb, R. N. Diurnal and nocturnal effects of brimonidine monotherapy on intraocular pressure. Ophthalmology 117, 2075–2079 (2010).

    Article  PubMed  Google Scholar 

  66. Toris, C. B., Gleason, M. L., Camras, C. B. & Yablonski, M. E. Effects of brimonidine on aqueous humor dynamics in human eyes. Arch. Ophthalmol. 113, 1514–1517 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Hernandez, M., Urcola, J. H. & Vecino, E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp. Eye Res. 86, 798–806 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Edwards, A. O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Li, M. et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nature Genet. 38, 1049–1054 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Maller, J. et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nature Genet. 38, 1055–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Yates, J. R. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 357, 553–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Fagerness, J. A. et al. Variation near complement factor I is associated with risk of advanced AMD. Eur. J. Hum. Genet. 17, 100–104 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Cousins, S. W. & the Ophthotech Study Group. Targeting complement factor 5 in combination with vascular endothelial growth factor (VEGF) inhibition for neovascular age related macular degeneration (AMD): results of a Phase 1 study. Invest. Ophthalmol. Vis. Sci. 51, e-Abstract 1251 (2010).

    Google Scholar 

  76. Mata, N. L., Weng, J. & Travis, G. H. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc. Natl Acad. Sci. USA 97, 7154–7159 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sparrow, J. R., Nakanishi, K. & Parish, C. A. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest. Ophthalmol. Vis. Sci. 41, 1981–1989 (2000).

    CAS  PubMed  Google Scholar 

  78. Kubota, R. et al. Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator. Retina 32, 183–188 (2012).

    Article  PubMed  Google Scholar 

  79. Weng, J. et al. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 98, 13–23 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Land, S. C. & Tee, A. R. Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J. Biol. Chem. 282, 20534–20543 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Brafman, A. et al. Inhibition of oxygen-induced retinopathy in RTP801-deficient mice. Invest. Ophthalmol. Vis. Sci. 45, 3796–3805 (2004).

    Article  PubMed  Google Scholar 

  82. Kleinman, M. E. et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature Med. 11, 263–270 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Sledz, C. A., Holko, M., de Veer, M. J., Silverman, R. H. & Williams, B. R. Activation of the interferon system by short-interfering RNAs. Nature Cell Biol. 5, 834–839 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Dawson, D. W. et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285, 245–248 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Bhutto, I. A. et al. Reduction of endogenous angiogenesis inhibitors in Bruch's membrane of the submacular region in eyes with age-related macular degeneration. Arch. Ophthalmol. 126, 670–678 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Holekamp, N. M., Bouck, N. & Volpert, O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am. J. Ophthalmol. 134, 220–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Maclachlan, T. K. et al. Preclinical safety evaluation of AAV2-sFLT01— a gene therapy for age-related macular degeneration. Mol. Ther. 19, 326–334 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Kendall, R. L. & Thomas, K. A. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl Acad. Sci. USA 90, 10705–10709 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ambati, B. K. et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 443, 993–997 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Takeda, A. et al. CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 460, 225–230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Takahashi, K., Saishin, Y., King, A. G., Levin, R. & Campochiaro, P. A. Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. Arch. Ophthalmol. 127, 494–499 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. LaVail, M. M. et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest. Ophthalmol. Vis. Sci. 39, 592–602 (1998).

    CAS  PubMed  Google Scholar 

  95. Palanki, M. S. et al. Development of prodrug 4-chloro-3-(5-methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotria zin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration. J. Med. Chem. 51, 1546–1559 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Heeschen, C., Weis, M., Aicher, A., Dimmeler, S. & Cooke, J. P. A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. J. Clin. Invest. 110, 527–536 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kiuchi, K. et al. Mecamylamine suppresses basal and nicotine-stimulated choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 49, 1705–1711 (2008).

    Article  PubMed  Google Scholar 

  98. Campochiaro, P. A. et al. Topical mecamylamine for diabetic macular edema. Am. J. Ophthalmol. 149, 839–851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ozaki, H., Hla, T. & Lee, M. J. Sphingosine-1-phosphate signaling in endothelial activation. J. Atheroscler. Thromb. 10, 125–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Watterson, K. R., Lanning, D. A., Diegelmann, R. F. & Spiegel, S. Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing. Wound Repair Regen. 15, 607–616 (2007).

    Article  PubMed  Google Scholar 

  101. Caballero, S. et al. Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization. Exp. Eye Res. 88, 367–377 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Xie, B. et al. Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization. J. Cell Physiol. 218, 192–198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Orecchia, A. et al. Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the α5β1 integrin. J. Cell Sci. 116, 3479–3489 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Zahn, G. et al. Preclinical evaluation of the novel small-molecule integrin α5β1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization. Arch. Ophthalmol. 127, 1329–1335 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Nirmalan, P. K. et al. Relationship between vision impairment and eye disease to vision-specific quality of life and function in rural India: the Aravind Comprehensive Eye Survey. Invest. Ophthalmol. Vis. Sci. 46, 2308–2312 (2005).

    Article  PubMed  Google Scholar 

  106. Pettit, G. R. et al. Antineoplastic agents 322. synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des. 10, 299–309 (1995).

    CAS  PubMed  Google Scholar 

  107. Dark, G. G. et al. Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res. 57, 1829–1834 (1997).

    CAS  PubMed  Google Scholar 

  108. Nambu, H., Nambu, R., Melia, M. & Campochiaro, P. A. Combretastatin A-4 phosphate suppresses development and induces regression of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 44, 3650–3655 (2003).

    Article  PubMed  Google Scholar 

  109. Griggs, J. et al. Inhibition of proliferative retinopathy by the anti-vascular agent combretastatin-A4. Am. J. Pathol. 160, 1097–1103 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Benjamin, L. E., Hemo, I. & Keshet, E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591–1598 (1998).

    CAS  PubMed  Google Scholar 

  111. Jo, N. et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am. J. Pathol. 168, 2036–2053 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Boyer, D. S. & the Ophthotech Anti-PDGF in AMD Study Group. Combined inhibition of platelet derived (PDGF) and vascular endothelial (VEGF) growth factors for the treatment of neovascular age-related macular degeneration (NV-AMD) — results of a Phase 1 study. Invest. Ophthalmol. Vis. Sci. 50, e-Abstract 1260 (2009).

    Google Scholar 

  113. Sit, A. J., Weinreb, R. N., Crowston, J. G., Kripke, D. F. & Liu, J. H. Sustained effect of travoprost on diurnal and nocturnal intraocular pressure. Am. J. Ophthalmol. 141, 1131–1133 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Liu, J. H. & Weinreb, R. N. Monitoring intraocular pressure for 24 h. Br. J. Ophthalmol. 95, 599–600 (2011).

    Article  PubMed  Google Scholar 

  115. Coue, M., Brenner, S. L., Spector, I. & Korn, E. D. Inhibition of actin polymerization by latrunculin A. FEBS Lett. 213, 316–318 (1987).

    Article  CAS  PubMed  Google Scholar 

  116. Peterson, J. A. et al. Latrunculins' effects on intraocular pressure, aqueous humor flow, and corneal endothelium. Invest. Ophthalmol. Vis. Sci. 41, 1749–1758 (2000).

    CAS  PubMed  Google Scholar 

  117. Chen, J., Runyan, S. A. & Robinson, M. R. Novel ocular antihypertensive compounds in clinical trials. Clin. Ophthalmol. 5, 667–677 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Rao, P. V., Deng, P. F., Kumar, J. & Epstein, D. L. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest. Ophthalmol. Vis. Sci. 42, 1029–1037 (2001).

    CAS  PubMed  Google Scholar 

  119. Honjo, M. The possibility of selective Rho-associated kinase (ROCK) inhibitors as a medical treatment for glaucoma. [Article in Japanese] Nihon Ganka Gakkai Zasshi 113, 1071–1081 (2009).

    CAS  PubMed  Google Scholar 

  120. Williams, R. D., Novack, G. D., van Haarlem, T. & Kopczynski, C. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am. J. Ophthalmol. 152, 834–841 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Wirostko B. M., Umeno, H., Hsu, H. H. & Kengatharan, M. Safety and efficacy of a novel topical Rho kinase inhibitor ATS907 in normotensive cynomolgus monkeys. Invest. Ophthalmol. Vis. Sci. 52, e-Abstract 3096 (2011).

    Google Scholar 

  122. Yamamoto, T., Abe, H., Kuwayama, Y., Tanihara, H. & Araie, M. Efficacy and safety of the Rho kinase inhibitor, K-115, over 24 hours in patients with primary open-angle glaucoma and ocular hypertension. Invest. Ophthalmol. Vis. Sci. 52, e-Abstract 216 (2011).

    Article  Google Scholar 

  123. Mizuno, K. et al. Ocular hypotensive mechanism of K-115, a Rho-kinase inhibitor, and Rho-kinase expression in the eye. Invest. Ophthalmol. Vis. Sci. 52, e-Abstract 237 (2011).

    Article  CAS  Google Scholar 

  124. Sugiyama, T. et al. Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest. Ophthalmol. Vis. Sci. 52, 64–69 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Honjo, M. et al. Potential role of Rho-associated protein kinase inhibitor Y-27632 in glaucoma filtration surgery. Invest. Ophthalmol. Vis. Sci. 48, 5549–5557 (2007).

    Article  PubMed  Google Scholar 

  126. Tian, B., Gabelt, B. T., Crosson, C. E. & Kaufman, P. L. Effects of adenosine agonists on intraocular pressure and aqueous humor dynamics in cynomolgus monkeys. Exp. Eye Res. 64, 979–989 (1997).

    Article  CAS  PubMed  Google Scholar 

  127. Wang, R. F., Podos, S. M., Mittag, T. W. & Yokoyoma, T. Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes. Exp. Eye Res. 80, 629–632 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Chien, F. Y., Wang, R. F., Mittag, T. W. & Podos, S. M. Effect of WIN 55212-2, a cannabinoid receptor agonist, on aqueous humor dynamics in monkeys. Arch. Ophthalmol. 121, 87–90 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Hepler, R. S. & Frank, I. R. Marihuana smoking and intraocular pressure. JAMA 217, 1392 (1971).

    Article  CAS  PubMed  Google Scholar 

  130. Ruz, V., Moreno-Montañés, J., Sadaba, B., González, V. & Jiménez, A. I. Phase I study with a new siRNA: SYL040012. Tolerance and effect on intraocular pressure. Invest. Ophthalmol. Vis. Sci. 52, e-Abstract 223 (2011).

    Article  Google Scholar 

  131. Schachar, R. A., Raber, S., Courtney, R. & Zhang, M. A Phase 2, randomized, dose-response trial of taprenepag isopropyl (PF-04217329) versus latanoprost 0.005% in open-angle glaucoma and ocular hypertension. Curr. Eye Res. 36, 809–817 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Schachar, R. A., Raber, S., Courtney, R., Zhang, M. & Bosworth, C. Dose-escalating, double-masked, vehicle-controlled trial of the IOP-reducing effect of the EP2 agonist PF-04217329. Invest. Ophthalmol. Vis. Sci. 51, e-Abstract 175 (2010).

    Google Scholar 

  133. Goldberg, D. F. & Williams, R. A Phase 2 study evaluating safety and efficacy of the latanoprost punctal plug delivery system (L-PPDS) in subjects with ocular hypertension (OH) or open-angle glaucoma (OAG). Invest. Ophthalmol. Vis. Sci. 53, e-Abstract 5095 (2012).

    Article  Google Scholar 

  134. Clark, A. F. & Yorio, T. Ophthalmic drug discovery. Nature Rev. Drug Discov. 2, 448–459 (2003).

    Article  CAS  Google Scholar 

  135. Mauler, F. & Horvath, E. Neuroprotective efficacy of repinotan HCl, a 5-HT1A receptor agonist, in animal models of stroke and traumatic brain injury. J. Cereb. Blood Flow Metab. 25, 451–459 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Ramos, A. J. et al. The 5HT1A receptor agonist, 8-OH-DPAT, protects neurons and reduces astroglial reaction after ischemic damage caused by cortical devascularization. Brain Res. 1030, 201–220 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Adayev, T., Ray, I., Sondhi, R., Sobocki, T. & Banerjee, P. The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Cα. Biochim. Biophys. Acta 1640, 85–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Hsiung, S. C., Tamir, H., Franke, T. F. & Liu, K. P. Roles of extracellular signal-regulated kinase and Akt signaling in coordinating nuclear transcription factor-κB-dependent cell survival after serotonin 1A receptor activation. J. Neurochem. 95, 1653–1666 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Collier, R. J. et al. Agonists at the serotonin receptor (5-HT1A) protect the retina from severe photo-oxidative stress. Invest. Ophthalmol. Vis. Sci. 52, 2118–2126 (2011).

    Article  CAS  PubMed  Google Scholar 

  140. Wen, R., Cheng, T., Li, Y., Cao, W. & Steinberg, R. H. α2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage. J. Neurosci. 16, 5986–5992 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Johnson, L. V. et al. The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc. Natl Acad. Sci. USA 99, 11830–11835 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ding, J. D. et al. Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-β antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res. 48, 339–345 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Faktorovich, E. G., Steinberg, R. H., Yasumura, D., Matthes, M. T. & LaVail, M. M. Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 347, 83–86 (1990).

    Article  CAS  PubMed  Google Scholar 

  144. Fuhrmann, S., Kirsch, M. & Hofmann, H. D. Ciliary neurotrophic factor promotes chick photoreceptor development in vitro. Development 121, 2695–2706 (1995).

    CAS  PubMed  Google Scholar 

  145. Fuhrmann, S., Grabosch, K., Kirsch, M. & Hofmann, H. D. Distribution of CNTF receptor α protein in the central nervous system of the chick embryo. J. Comp. Neurol. 461, 111–122 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Tao, W. et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 43, 3292–3298 (2002).

    PubMed  Google Scholar 

  147. LaVail, M. M. et al. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc. Natl Acad. Sci. USA 89, 11249–11253 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cayouette, M. & Gravel, C. Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum. Gene Ther. 8, 423–430 (1997).

    Article  CAS  PubMed  Google Scholar 

  149. Cayouette, M., Behn, D., Sendtner, M., Lachapelle, P. & Gravel, C. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J. Neurosci. 18, 9282–9293 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhang, K. et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc. Natl Acad. Sci. USA 108, 6241–6245 (2011). This is the first study to demonstrate neuroprotection by CNTF in a Phase II clinical trial.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Lambert, W. S., Ruiz, L., Crish, S. D., Wheeler, L. A. & Calkins, D. J. Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons. Mol. Neurodegener. 6, 4 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. WoldeMussie, E., Ruiz, G., Wijono, M. & Wheeler, L. A. Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest. Ophthalmol. Vis. Sci. 42, 2849–2855 (2001).

    CAS  PubMed  Google Scholar 

  153. Krupin, T., Liebmann, J. M., Greenfield, D. S., Ritch, R. & Gardiner, S. A randomized trial of brimonidine versus timolol in preserving visual function: results from the low-pressure glaucoma treatment study. Am. J. Ophthalmol. 151, 671–681 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Drance, S. M., Schulzer, M., Thomas, B. & Douglas, G. R. Multivariate analysis in glaucoma. Use of discriminant analysis in predicting glaucomatous visual field damage. Arch. Ophthalmol. 99, 1019–1022 (1981).

    Article  CAS  PubMed  Google Scholar 

  155. Wolfs, R. C. et al. Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch. Ophthalmol. 116, 1640–1645 (1998).

    Article  CAS  PubMed  Google Scholar 

  156. Wiggs, J. L. Genetic etiologies of glaucoma. Arch. Ophthalmol. 125, 30–37 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Stone, E. M. et al. Identification of a gene that causes primary open angle glaucoma. Science 275, 668–670 (1997).

    Article  CAS  PubMed  Google Scholar 

  158. Ramdas, W. D. et al. Common genetic variants associated with open-angle glaucoma. Hum. Mol. Genet. 20, 2464–2471 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Burdon, K. P. et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nature Genet. 43, 574–578 (2011).

    Article  CAS  PubMed  Google Scholar 

  160. Hietala, K., Forsblom, C., Summanen, P. & Groop, P. H. Heritability of proliferative diabetic retinopathy. Diabetes 57, 2176–2180 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Arar, N. H. et al. Heritability of the severity of diabetic retinopathy: the FIND-Eye study. Invest. Ophthalmol. Vis. Sci. 49, 3839–3845 (2008).

    Article  PubMed  Google Scholar 

  162. Wong, T. Y. et al. Diabetic retinopathy in a multi-ethnic cohort in the United States. Am. J. Ophthalmol. 141, 446–455 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Tong, Z. et al. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc. Natl Acad. Sci. USA 105, 6998–7003 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Chen, Y. et al. Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors. Arch. Ophthalmol. 129, 344–351 (2011). This is a good survey on the genetic and environmental factors that influence AMD.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Neale, B. M. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl Acad. Sci. USA 107, 7395–7400 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Klaver, C. C. et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am. J. Hum. Genet. 63, 200–206 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bainbridge, J. W. et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358, 2231–2239 (2008). This is one of the first studies to demonstrate the efficacy of gene therapy in patients with limited visual function owing to retinal disease.

    Article  CAS  PubMed  Google Scholar 

  168. Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358, 2240–2248 (2008). This is one of the first studies to demonstrate the efficacy of gene therapy in patients with limited visual function owing to retinal disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Cideciyan, A. V. et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc. Natl Acad. Sci. USA 105, 15112–15117 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Deng, W. T. et al. Tyrosine-mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats. Invest. Ophthalmol. Vis. Sci. 53, 1895–1904 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Hughes, A. E. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genet. 38, 1173–1177 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Hageman, G. S. 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. 38, 592–604 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Du, H., Lim, S. L., Grob, S. & Zhang, K. Induced pluripotent stem cell therapies for geographic atrophy of age-related macular degeneration. Semin. Ophthalmol. 26, 216–224 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Zhang, K. & Ding, S. Stem cells and eye development. N. Engl. J. Med. 365, 370–372 (2011). This is a summary and review of eye development and its relevance to stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kim, J. et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc. Natl Acad. Sci. USA 108, 7838–7843 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Gouras, P., Kong, J. & Tsang, S. H. Retinal degeneration and RPE transplantation in Rpe65−/− mice. Invest. Ophthalmol. Vis. Sci. 43, 3307–3311 (2002).

    PubMed  Google Scholar 

  177. Urtti, A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv. Drug Deliv. Rev. 58, 1131–1135 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Thrimawithana, T. R., Young, S., Bunt, C. R., Green, C. & Alany, R. G. Drug delivery to the posterior segment of the eye. Drug Discov. Today 16, 270–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  179. Burnham, C. M. Encapsulated cell technology could prevent blindness. Drug Discov. Today 8, 146–147 (2003).

    Article  PubMed  Google Scholar 

  180. Tao, W. Application of encapsulated cell technology for retinal degenerative diseases. Expert Opin. Biol. Ther. 6, 717–726 (2006).

    Article  CAS  PubMed  Google Scholar 

  181. Sieving, P. A. et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc. Natl Acad. Sci. USA 103, 3896–3901 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhang, R. et al. Intravitreal cell-based production of glucagon-like peptide-1. Retina 31, 785–789 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nature Rev. Drug Discov. 9, 615–627 (2010). This is an excellent review on the rational design of therapeutic nanoparticles.

    Article  CAS  Google Scholar 

  184. Shi, J., Votruba, A. R., Farokhzad, O. C. & Langer, R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 10, 3223–3230 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sultana, Y., Maurya, D. P., Iqbal, Z. & Aqil, M. Nanotechnology in ocular delivery: current and future directions. Drugs Today 47, 441–455 (2011).

    Article  CAS  Google Scholar 

  186. Zhang, L. et al. Nanoparticles in medicine: therapeutic applications and developments. Clin. Pharmacol. Ther. 83, 761–769 (2008). This is a good overview of the development and clinical approval of nanomedicines.

    Article  CAS  PubMed  Google Scholar 

  187. Yan, M. et al. A novel intracellular protein delivery platform based on single-protein nanocapsules. Nature Nanotechnol. 5, 48–53 (2010).

    Article  CAS  Google Scholar 

  188. Gariano, R. F. & Gardner, T. W. Retinal angiogenesis in development and disease. Nature 438, 960–966 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nature Rev. Drug Discov. 8, 129–138 (2009).

    Article  CAS  Google Scholar 

  190. du Toit, L. C., Pillay, V., Choonara, Y. E., Govender, T. & Carmichael, T. Ocular drug delivery — a look towards nanobioadhesives. Expert Opin. Drug Deliv. 8, 71–94 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Hu, C.-M. J. et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl Acad. Sci. USA 108, 10980–10985 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Weinreb, R. N. & Lindsey, J. D. Metalloproteinase gene transcription in human ciliary muscle cells with latanoprost. Invest. Ophthalmol. Vis. Sci. 43, 716–722 (2002).

    PubMed  Google Scholar 

  193. Hiett, J. A. & Dockter, C. A. Topical carbonic anhydrase inhibitors: a new perspective in glaucoma therapy. Optom. Clin. 2, 97–112 (1992).

    CAS  PubMed  Google Scholar 

  194. Nilsson, S. F. et al. The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey. Invest. Ophthalmol. Vis. Sci. 47, 4042–4049 (2006).

    Article  PubMed  Google Scholar 

  195. Krauss, A. H. et al. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp. Eye Res. 93, 250–255 (2011).

    Article  CAS  PubMed  Google Scholar 

  196. Choudhri S., Wand, M. & Shields, M. B. A comparison of dorzolamide–timolol combination versus the concomitant drugs. Am. J. Ophthalmol. 130, 832–833 (2000).

    Article  CAS  PubMed  Google Scholar 

  197. Craven, E. R. et al. Brimonidine and timolol fixed-combination therapy versus montherapy: a 3-month randomized trial in patients with glaucoma or ocular hypertension. J. Ocul. Pharmacol. Ther. 21, 337–338 (2005).

    Article  CAS  PubMed  Google Scholar 

  198. Pfeiffer, N. & the German Latanoprost Fixed Combination Study Group. A comparison of the fixed combination of latanoprost and timolol with its individual components. Graefe's Arch. Clin. Exp. Ophthalmol. 240, 893–899 (2002).

    Article  CAS  Google Scholar 

  199. Higginbotham, E. J. et al. Latanoprost and timolol combination therapy vs monotherapy: one-year randomized trial. Arch. Ophthalmol. 120, 915–922 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Barneby, H. S. et al. The safety and efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution. Am. J. Ophthalmol. 140, 1–7 (2005).

    Google Scholar 

  201. Schuman, J. S. et al. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am. J. Ophthalmol. 140, 242–250 (2005).

    Article  CAS  PubMed  Google Scholar 

  202. Hommer A & the Ganfort Investigators Group I. A double-masked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed combination use in patients with glaucoma or ocular hypertension. Eur. J. Ophthalmol. 17, 53–62 (2007).

    Article  CAS  PubMed  Google Scholar 

  203. Rhéaume, M. A. & Vavvas, D. Pharmacologic vitreolysis. Semin. Ophthalmol. 25, 295–302 (2010).

    Article  PubMed  Google Scholar 

  204. Gandorfer, A. et al. Posterior vitreous detachment induced by microplasmin. Invest. Ophthalmol. Vis. Sci. 45, 641–647 (2004).

    Article  PubMed  Google Scholar 

  205. Pieramici, D. J. & Boyer, D. S. The phase III MIVI-TRUST clinical trial data: subgroup analysis of a single intravitreal injection of ocriplasmin in patients with full-thickness macular hole (Poster). In The Annu. Meeting of The Assoc. for Research in Vision and Ophthalmology (ARVO) (6–10 May 2012; Ft. Lauderdale, Florida, USA).

    Google Scholar 

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Acknowledgements

We thank J. Ambati, S. Ding, I. Kozak, J. Lee, L. Zhao and P. Shaw for their helpful comments. K.Z. is supported by grants from the Chinese National 985 Project to Sichuan University and West China Hospital, the National Eye Institute and the US National Institutes of Health, VA Merit Award, Research to Prevent Blindness, King Abdulaziz City for Science and Technology (through the University of California San Diego Center of Excellence in Nanomedicine centre grant) and the BWF (Burroughs Wellcome Fund) Clinical Scientist Award in Translational Research. L.Z. is supported by the National Science Foundation (NSF) grants CMMI1031239 and DMR1216461; R.N.W. is supported by grants from the National Eye Institute and the US National Institutes of Health (EY019692) and an unrestricted grant from Research to Prevent Blindness, New York, USA. We apologize for the omission of references owing to page limitations.

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Correspondence to Kang Zhang.

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Robert Weinreb is a consultant for Alcon, Allergan, Altheos, Amakem NV, Bausch and Lomb, Genentech, Merck, Novartis and Quark. He has received lecture honoraria or travel reimbursement from Alcon, Allergan, Bausch and Lomb, Merck and Genentech.

Kang Zhang is a consultant for Genentech, ThromboGenics and Acucela. He has received grants from the US National Institutes of Health, Genentech, the VA Merit Award and the Burroughs Wellcome Fund.

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Glossary

Age-related macular degeneration

(AMD). A disease process that is characterized by the degeneration of photoreceptor cells in the macula, leading to loss of central vision.

Diabetic retinopathy

A microvascular complication of type 2 diabetes that is characterized by increased vascular permeability in the initial stages of disease.

Glaucoma

A progressive disease that is characterized by optic disc cupping and peripheral visual field loss.

Retinal pigment epithelium

(RPE). A monolayer of pigmented cells in the retina, located between the photoreceptor cells and choroid.

Macula

A highly pigmented area near the centre of the retina that is responsible for detailed central vision.

Geographic atrophy

An advanced form of age-related macular degeneration that is characterized by the atrophy of retinal pigment epithelium and photoreceptor cells.

Choroidal neovascularization

(CNV). An advanced form of age-related macular degeneration that is characterized by the growth of abnormal blood vessels into the subretinal space.

Intraocular pressure

(IOP). The fluid pressure inside the eye, which is determined by the production and drainage of aqueous humour.

Aqueous humour

A clear, watery fluid produced by the ciliary epithelium that fills the anterior and posterior chambers of the eye.

Complement system

A part of the innate immune system that consists of approximately 25 proteins. Three pathways activate the complement system: the classical complement pathway, the alternative complement pathway and the mannose-binding pathway.

Small interfering RNA

(siRNA). Small, double-stranded RNA molecules that interfere with gene expression by binding to and promoting the degradation of mRNA.

Nanotechnology

The understanding and control of matter at dimensions between approximately 1 nm and 100 nm. It involves imaging, measuring, modelling and manipulating matter at this length scale.

Nanoparticle drugs

Nanometre-scale particles that are used to carry and transport pharmaceutical agents to improve therapeutic efficacy, drug safety and patient compliance.

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Zhang, K., Zhang, L. & Weinreb, R. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov 11, 541–559 (2012). https://doi.org/10.1038/nrd3745

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