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Glaucoma - Next Generation Therapeutics: Impossible to Possible

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Abstract

The future of next generation therapeutics for glaucoma is strong. The recent approval of two novel intraocular pressure (IOP)-lowering drugs with distinct mechanisms of action is the first in over 20 years. However, these are still being administered as topical drops. Efforts are underway to increase patient compliance and greater therapeutic benefits with the development of sustained delivery technologies. Furthermore, innovations from biologics- and gene therapy-based therapeutics are being developed in the context of disease modification, which are expected to lead to more permanent therapies for patients. Neuroprotection, including the preservation of retinal ganglion cells (RGCs) and optic nerve is another area that is actively being explored for therapeutic options. With improvements in imaging technologies and determination of new surrogate clinical endpoints, the therapeutic potential for translation of neuroprotectants is coming close to clinical realization. This review summarizes the aforementioned topics and other related aspects.

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References

  1. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(12):e1221–34.

    PubMed  Google Scholar 

  2. Schehlein EM, Novack G, Robin AL. New pharmacotherapy for the treatment of glaucoma. Expert Opin Pharmacother. 2017;18(18):1939–46.

    CAS  PubMed  Google Scholar 

  3. MacKean JM, Elkington AR. Compliance with treatment of patients with chronic open-angle glaucoma. Br J Ophthalmol. 1983;67(1):46–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Gurwitz JH, Glynn RJ, Monane M, Everitt DE, Gilden D, Smith N, et al. Treatment for glaucoma: adherence by the elderly. Am J Public Health. 1993;83(5):711–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Okeke CO, Quigley HA, Jampel HD, Ying GS, Plyler RJ, Jiang Y, et al. Adherence with topical glaucoma medication monitored electronically the Travatan dosing aid study. Ophthalmology. 2009;116(2):191–9.

    PubMed  Google Scholar 

  6. Newman-Casey PA, Robin AL, Blachley T, Farris K, Heisler M, Resnicow K, et al. The Most common barriers to Glaucoma medication adherence: a cross-sectional survey. Ophthalmology. 2015;122(7):1308–16.

    PubMed  Google Scholar 

  7. Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of Eyedrop instillation in patients with Glaucoma. Arch Ophthalmol. 2009;127(6):732–6.

    PubMed  Google Scholar 

  8. Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension an evidence-based review. Ophthalmology. 2005;112(6):953–61.

    PubMed  Google Scholar 

  9. Jampel H. Target IOP in clinical practice. In: Weinreb RN, Brandt JD, Garway-Heath D, Madeiros FA, editors. Intraocular pressure. Amsterdam: Kugler Publications; 2007. p. 121–5.

    Google Scholar 

  10. Prum BE Jr, Rosenberg LF, Gedde SJ, Mansberger SL, Stein JD, Moroi SE, et al. Primary Open-angle glaucoma preferred practice pattern(®) guidelines. Ophthalmology. 2016;123(1):41–111.

    Google Scholar 

  11. Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9(2):134–42.

    CAS  PubMed  Google Scholar 

  12. Dunbar GE, Shen BY, Aref AA. The Sensimed triggerfish contact lens sensor: efficacy, safety, and patient perspectives. Clin Ophthalmol. 2017;11:875–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Food and Drug Administration. Available from: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm489308.htm (accessed on September 24, 2018).

  14. Food and Drug Administration. Available from: https://clinicaltrials.gov/ct2/results?cond=&term=Bimatoprost+Sustained+release+allergan. Last accessed on August 21, 2018).

  15. Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87(12):1479–88.

    CAS  PubMed  Google Scholar 

  16. Nomoto H, Shiraga F, Kuno N, Kimura E, Fujii S, Shinomiya K, et al. Pharmacokinetics of bevacizumab after topical, subconjunctival, and intravitreal Administration in Rabbits. Invest Ophthalmol Vis Sci. 2009;50(10):4807–13.

    PubMed  Google Scholar 

  17. Guymer C, Wood JP, Chidlow G, Casson RJ. Neuroprotection in glaucoma: recent advances and clinical translation. Clin Exp Ophthalmol. 2018; (published ahead of print). https://doi.org/10.1111/ceo.13336.

  18. Tanna AP, Johnson M. Rho kinase inhibitors as a novel treatment for Glaucoma and ocular hypertension. Ophthalmology. 2018;125(11):1741–56.

    PubMed  Google Scholar 

  19. Prasanna G, Li B, Mogi M, Rice DS. Pharmacology of novel intraocular pressure-lowering targets that enhance conventional outflow facility: pitfalls, promises and what lies ahead? Eur J Pharmacol. 2016;787:47–56.

    CAS  PubMed  Google Scholar 

  20. Cavet ME, DeCory HH. The role of nitric oxide in the intraocular Pressure lowering efficacy of Latanoprostene Bunod: review of nonclinical studies. J Ocul Pharmacol Ther. 2018;34(1–2):52–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014;55(8):5005–15.

    CAS  PubMed  Google Scholar 

  22. Wang SK, Chang RT. An emerging treatment option for glaucoma: rho kinase inhibitors. Clin Ophthalmol. 2014;8:883–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Alm A. Latanoprost in the treatment of glaucoma. Clin Ophthalmol. 2014;8:1967–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Shahidullah M, Mandal A, Wei G, Delamere NA. Nitric oxide regulation of Na, K-ATPase activity in ocular ciliary epithelium involves Src family kinase. J Cell Physiol. 2014;229(3):343–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Krauss AH, Impagnatiello F, Toris CB, Gale DC, Prasanna G, Borghi V, et al. Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models. Exp Eye Res. 2011;93(3):250–5.

    CAS  PubMed  Google Scholar 

  26. Saeki T, Tsuruga H, Aihara M, Araie M, Rittenhouse K. ARVO annual meeting abstract. Invest Ophthalmol Vis Sci. 2009;50(13):4064.

    Google Scholar 

  27. Hoy SM. Latanoprostene Bunod ophthalmic solution 0.024%: a review in open-angle Glaucoma and ocular hypertension. Drugs. 2018;78(7):773–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Weinreb RN, Ong T, Scassellati Sforzolini B, Vittitow JL, Singh K, Kaufman PL. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015;99(6):738–45.

    PubMed  Google Scholar 

  29. Weinreb RN, Scassellati Sforzolini B, Vittitow J, Liebmann J. Latanoprostene Bunod 0.024% versus Timolol maleate 0.5% in subjects with open-angle Glaucoma or ocular hypertension: the APOLLO study. Ophthalmology. 2016;123(5):965–73.

    PubMed  Google Scholar 

  30. Medeiros FA, Martin KR, Peace J, Scassellati Sforzolini B, Vittitow JL, Weinreb RN. Comparison of Latanoprostene Bunod 0.024% and Timolol maleate 0.5% in open-angle Glaucoma or ocular hypertension: the LUNAR study. Am J Ophthalmol. 2016;168:250–9.

    CAS  PubMed  Google Scholar 

  31. Kawase K, Vittitow JL, Weinreb RN, Araie M. Long-term safety and efficacy of Latanoprostene Bunod 0.024% in Japanese subjects with open-angle glaucoma or ocular hypertension: the Jupiter study. Adv Ther. 2016;33(9):1612–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Inoue K, Setogawa A, Tomita G. Nonresponders to prostaglandin analogs among Normal-tension Glaucoma patients. J Ocul Pharmacol Ther. 2016;32(2):90–6.

    CAS  PubMed  Google Scholar 

  33. Enoki M, Saito J, Hara M, Uchida T, Sagara T, Nishida T. Additional reduction in intraocular pressure achieved with latanoprost in normal-tension glaucoma patients previously treated with unoprostone. Jpn J Ophthalmol. 2006;50(4):334–7.

    PubMed  Google Scholar 

  34. Agvald P, Adding LC, Gustafsson LE, Persson MG. Nitric oxide generation, tachyphylaxis and cross-tachyphylaxis from nitrovasodilators in vivo. Eur J Pharmacol. 1999;385(2–3):137–45.

    CAS  PubMed  Google Scholar 

  35. Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J Glaucoma. 2015;24(1):51–4.

    PubMed  Google Scholar 

  36. Kazemi A, McLaren JW, Kopczynski CC, Heah TG, Novack GD, Sit AJ. The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans. J Ocul Pharmacol Ther. 2018;34(5):380–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. 2015;122(2):302–7.

    PubMed  Google Scholar 

  38. Serle JB, Katz LJ, McLaurin E, Heah T, Ramirez-Davis N, Usner DW, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: rho kinase elevated iop treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116–27.

    CAS  PubMed  Google Scholar 

  39. Lewis RA, Levy B, Ramirez N, Kopczynski CC, Usner DW, Novack GD. Fixed-dose combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, controlled study in patients with open-angle glaucoma or ocular hypertension. Br J Ophthalmol. 2016;100(3):339–44.

    PubMed  Google Scholar 

  40. Grant WM. Tonographic method for measuring the facility and rate of aqueous flow in human eyes. Arch Ophth 19050;44(2):204–214.

  41. Saraswathy S, Tan JC, Yu F, Francis BA, Hinton DR, Weinreb RN, et al. Aqueous angiography: real-time and physiologic aqueous humor outflow imaging. PLoS One. 2016;11(1):e0147176.

    PubMed  PubMed Central  Google Scholar 

  42. Huang AS, Li M, Yang D, Wang H, Wang N, Weinreb RN. Aqueous angiography in living nonhuman Primates shows segmental, pulsatile, and dynamic angiographic aqueous humor outflow. Ophthalmology. 2017;124(6):793–803.

    PubMed  Google Scholar 

  43. Shi G, Fu L, Li X, Jiang C, Zhang Y. Morphological changes in Schlemm's canal in treated and newly diagnosed untreated glaucomatous eyes. Sci China Life Sci. 2014;57(12):1213–7.

    PubMed  Google Scholar 

  44. Yan X, Li M, Chen Z, Zhu Y, Song Y, Zhang H. Schlemm's canal and trabecular meshwork in eyes with primary open angle Glaucoma: a comparative study using high-frequency ultrasound biomicroscopy. PLoS One. 2016;11(1):e0145824.

    PubMed  PubMed Central  Google Scholar 

  45. Chen Z, Sun J, Li M, Liu S, Chen L, Jing S, et al. Effect of age on the morphologies of the human Schlemm's canal and trabecular meshwork measured with swept-source optical coherence tomography. Eye (Lond). 2018;32:1621–8.

    Google Scholar 

  46. Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121(1):48–56.

    PubMed  Google Scholar 

  47. Garway-Heath DF, Crabb DP, Bunce C, Lascaratos G, Amalfitano F, Anand N, et al. Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 2015;385(9975):1295–304.

    CAS  PubMed  Google Scholar 

  48. Drance SM. Diurnal variation of intraocular pressure in treated glaucoma. Significance in patients with chronic simple glaucoma. Arch Ophthalmol. 1963;70:302–11.

    CAS  PubMed  Google Scholar 

  49. De Moraes CG, Jasien JV, Simon-Zoula S, Liebmann JM, Ritch R. Visual field change and 24-hour IOP-related profile with a contact Lens sensor in treated Glaucoma patients. Ophthalmology. 2016;123(4):744–53.

    PubMed  Google Scholar 

  50. De Moraes CG, Mansouri K, Liebmann JM, Ritch R. Association between 24-hour intraocular Pressure monitored with contact Lens sensor and visual field progression in older adults with Glaucoma. JAMA Ophthalmol. 2018;136(7):779–85.

    PubMed  PubMed Central  Google Scholar 

  51. Kim JH, Caprioli J. Intraocular pressure fluctuation: is it important? J Ophthalmic Vis Res. 2018;3(2):170–4.

    Google Scholar 

  52. Stein JD, Shekhawat N, Talwar N, Balkrishnan R. Impact of the introduction of generic latanoprost on glaucoma medication adherence. Ophthalmology. 2015;122(4):738–47.

    PubMed  Google Scholar 

  53. Nordstrom BL, Friedman DS, Mozaffari E, Quigley HA, Walker AM. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005;140(4):598–606.

    PubMed  Google Scholar 

  54. Nouri-Mahdavi K, Hoffman D, Coleman AL, Liu G, Li G, Gaasterland D, et al. Predictive factors for glaucomatous visual field progression in the advanced glaucoma intervention study. Ophthalmology. 2004;111(9):1627–35.

    PubMed  Google Scholar 

  55. Quigley HA, Pollack IP, Harbin TS Jr. Long-term clinical trials and selected pharmacodynamics. Arch Ophthalmol. 1975;93(9):771–5.

    CAS  PubMed  Google Scholar 

  56. Food and Drug Administration. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017431 (accessed on September 24, 2018).

  57. Liu JHK, Weinreb RN. Monitoring intraocular pressure for 24 h. Br J Ophthalmol. 2011;95:599–600.

    PubMed  Google Scholar 

  58. Szigiato AA, Podbielski DW, Ahmed IIK. Sustained drug delivery for the management of glaucoma. Expert Rev Ophthalmol. 2011;12(2):173–86.

  59. Manickavasagam D, Oyewumi MO. Critical assessment of implantable drug delivery devices in glaucoma management. J Drug Deliv. 2013;2013:895013.

  60. Aref AA. Sustained drug delivery for glaucoma: current data and future trends. Curr Opin Ophthalmol. 2017;28:169–74.

    PubMed  Google Scholar 

  61. Food and Drug Administration. Available from: https://www.clinicaltrials.gov/ct2/home. (accessed on August 12th 2018).

  62. Brandt JD, Sall K, DuBiner H, Benza R, Alster Y, Walker G, et al. Six-month intraocular pressure reduction with a topical bimatoprost ocular insert: results of a phase II randomized controlled study. Ophthalmology. 2016;123(8):1685–94.

    PubMed  Google Scholar 

  63. Perera SA, Ting DS, Nongpiur ME, Chew PT, Aquino MCD, Sng CCA, et al. Feasibility study of sustained-release travoprost punctum plug for intraocular pressure reduction in an Asian population. Clin Ophthalmol. 2016;10:757–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Evans D, Repke C. Safety and efficacy of the latanoprost punctal plug delivery system (L-PPDS) in subjects with ocular hypertension (OH) or Open Angel Glaucoma (OAG). American Academy of Optometry Meeting Abstract 2012; Phoenix, AZ Program Number: 125689.

  65. Goldberg DF, Williams RA. 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). ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2012;53(14):5095.

  66. Lee SS, Hughes P, Ross AD, Robinson MR. Biodegradable implants for sustained drug release in the eye. Pharm Res. 2010;27(10):2043–53.

    CAS  PubMed  Google Scholar 

  67. Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121(10):1904–1914.

  68. Lewis RA, Christie WC, Day DG, Craven ER, Walters T, Bejanian M, et al. Bimatoprost sustained-release implants for Glaucoma therapy: 6-month results from a phase I/II clinical trial. Am J Ophthalmol. 2017;175(Mar):137–47.

    CAS  PubMed  Google Scholar 

  69. Seal J, Perera S, Coote M, Robinson MR, Hughes PM, Ghebremeskel AN, Burke JA, Attar M. Intracameral administration of a sustained release bimatoprost implant efficiently delivers bimatoprost to target tissue reducing risk of topical prostaglandin analog- associated adverse events. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2016;57(12):3022.

  70. Lee SS, Burke J, Shen J, Almazan A, Orilla W, Hughes P, et al. Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs. Vet Ophthalmol. 2018;21(4):376–81.

    CAS  PubMed  Google Scholar 

  71. Navratil T, Garcia A, Verhoeven RS, Trevino L, Gilger BC, Mansberger SL, Budenz DL, Ahmed IIK, Lewis RA, Yerxa BR. Advancing ENV515 (travoprost) intracameral implant into clinical development: nonclinical evaluation of ENV515 in support of first-time-in-human phase 2a clinical study. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2015;56(7):5706.

  72. Komaromy, AM, Koehl K, Harman, CD, Stewart SG, Wolinski, N, Norris TN, Valade D, Chekhtman I, Lambert JN, Donohue AC, Tait R. Long-term intraocular Pressure (IOP) control by means of a novel biodegradable intracameral (IC) latanoprost free acid (LFA) implant. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2017;58(8):4591.

  73. Mansberger SL, Conley J, Verhoeven RS, Blackwell K, Depenbusch M, Knox T, Walters TR, Ahmad I, Yerxa BR, Navratil T. Interim analysis of low dose ENV515 Travoprost XR with 11 month duration followed by dose escalation and 28 day efficacy evaluation of high dose ENV515. ARVO annual meeting abstract : invest. Ophthalmol. Vis. Sci. 2017;58(8):2110.

  74. Koehl K, Harman C, Stewart G, Wolinski N, Norris TN, Valade D, Donohue AC, Chekhtman I, Lambert JN, Tait R, Komaromy AM. Safety of a novel biodegradable intracameral (IC) latanoprost free acid (LFA) implant for long-term intraocular pressure (IOP) control. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2017;58(8):4592.

  75. Wong TT, Novack GD, Natarajan JV, Ho CL, Htoon HM, Venkatraman SS. Nanomedicine for glaucoma: sustained release latanoprost offers a new therapeutic option with substantial benefits over eyedrops. Drug Deliv and Transl Res. 2014;4(4):303–9.

    CAS  Google Scholar 

  76. Natarajan JV, Ang M, Darwitan A, Chattopadhyay S, Wong TT, Venkatraman SS. Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye. Int J Nanomedicine. 2012;7:123–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. It was publically reported that study terminated early due to manufacturer not replenishing study site supply of inserts, see: https://clinicaltrials.gov/ct2/show/NCT01180062. Last accessed on August 13, 2018.

  78. BioLight Life Sciences Inc. Available from: https://bio-light.co.il/eye-dtm-long-term-controlled-released-drug-delivery-technology/. Last accessed on August 21, 2018.

  79. Glaukos Corporation. January 2018. Available from: https://www.slideshare.net/glaukos/glaukos-january-2018-presentation. Last accessed on August 21, 2018.

  80. Food and Drug Administration. Available from: https://clinicaltrials.gov/ct2/show/NCT03519386. Last accessed on August 21, 2018.

  81. Ozdemir S, Wong TT, Allingham RR, Finkelstein EA. Predicted patient demand for a new delivery system for glaucoma medicine. Medicine (Baltimore). 2017;96(15):e6626.

    Google Scholar 

  82. Martínez T, González MV, Roehl I, Wright N, Pañeda C, Jiménez AI. In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of Glaucoma. Mol Ther. 2014;22(1):81–91.

    PubMed  Google Scholar 

  83. Hasenbach K, Bergen TV, Vandewalle E, Groef LD, Van Hove I, Moons L, et al. Potent and selective antisense oligonucleotides targeting the transforming growth factor beta (TGF-β) isoforms in advanced glaucoma: a preclinical evaluation. J Model Ophthalmol. 2016;1(2):20–8.

    Google Scholar 

  84. Jain A, Zode G, Kasetti RB, Ran FA, Yan W, Sharma TP, et al. CRISPR-Cas9-based treatment of myocilin associated glaucoma. Proc Natl Acad Sci U S A. 2017;114(42):11199–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Yun H, Zhou Y, Wills A, Du Y. Stem cells in the trabecular meshwork for regulating intraocular Pressure. J Ocul Pharmacol Ther. 2016;32(5):253–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhu W, Jain A, Gramlich OW, Tucker BA, Sheffield VC, Kuehn MH. Restoration of aqueous humor outflow following transplantation of iPSC derived trabecular meshwork cells in a transgenic mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2017;58(4):2054–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Moreno-Montañés J, Sádaba B, Ruz V, Gómez-Guiu A, Zarranz J, González MV, et al. Phase I clinical trial of SYL040012, a small interfering RNA targeting β-adrenergic receptor 2, for lowering intraocular Pressure. Mol Ther. 2014;22(1):226–32.

    PubMed  Google Scholar 

  88. Gonzalez V, Palumaa K, Turman K, Muñoz FJ, Jordan J, García J, Ussa F, Antón, A, Gutierrez E. Moreno-Montanes J. Phase 2 of bamosiran (SYL040012), a novel RNAi based compound for the treatment of increased intraocular pressure associated to glaucoma. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2014;55(13):564.

  89. Gonzalez V, Moreno-Montanes J, Oll M, Sall KN, Palumaa K, Dubiner H, Turman K, Muñoz-Negrete F, Ruz V, Jimenez AI. Results of phase IIB SYLTAG clinical trial with bamosiran in patients with glaucoma. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2016;57(12):3023.

  90. Cordeiro MF, Mead A, Ali RR, Alexander RA, Murray S, Chen C, et al. Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome. Gene Ther. 2003;10(1):59–71.

    CAS  PubMed  Google Scholar 

  91. Pfeiffer N, Voykov B, Renieri G, Bell K, Richter P, Weigel M, et al. First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in subjects with open-angle glaucoma undergoing glaucoma filtration surgery. PLoS One. 2017;12(11):e0188899.

    PubMed  PubMed Central  Google Scholar 

  92. Fleenor DL, Shepard AR, Hellberg PE, Jacobson N, Pang IH, Clark AF. TGFbeta2-induced changes in human trabecular meshwork: implications for intraocular pressure. Invest Ophthalmol Vis Sci. 2006;47(1):226–34.

    PubMed  Google Scholar 

  93. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.

    PubMed  PubMed Central  Google Scholar 

  94. Thiel MA, Wild A, Schmid MK, Job O, Bochmann F, Loukopoulos V, et al. Penetration of a topically administered anti–tumor necrosis factor alpha antibody fragment into the anterior chamber of the human eye. Ophthalmology. 2013;120(7):1403 1408.

    Google Scholar 

  95. Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018;24(7):939–46.

    CAS  PubMed  Google Scholar 

  96. Shaughnessy AF. Monoclonal antibodies: magic bullets with a hefty price tag. BMJ. 2012;345:e8346.

    PubMed  Google Scholar 

  97. Weinreb RN, Liebmann JM, Cioffi GA, Goldberg I, Brandt JD, Johnson CA, et al. Oral memantine for the treatment of glaucoma: design and results of 2 randomized, placebo-controlled, phase 3 studies. Ophthalmology. 2018; (published ahead of print);125:1874–85. https://doi.org/10.1016/j.ophtha.2018.06.017.

    Article  PubMed  Google Scholar 

  98. Quigley HA. Clinical trials for glaucoma neuroprotection are not impossible. Curr Opin Ophthalmol. 2012;23(2):144–54.

    PubMed  Google Scholar 

  99. Pease ME, Zack DJ, Berlinicke C, Bloom K, Cone F, Wang Y, et al. Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Invest Ophthalmol Vis Sci. 2009;50(5):2194–200.

    PubMed  Google Scholar 

  100. Johnson TV, Bull ND, Martin KR. Neurotrophic factor delivery as a protective treatment for glaucoma. Exp Eye Res. 2011;93(2):196–203.

    CAS  PubMed  Google Scholar 

  101. Kimura A, Namekata K, Guo X, Harada C, Harada T. Neuroprotection, growth factors and BDNF-TrkB signaling in retinal degeneration. Int J Mol Sci. 2016;17(9):E1584.

    PubMed  Google Scholar 

  102. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78.

    CAS  PubMed  Google Scholar 

  103. Tezel G, Yang X, Luo C, Kain AD, Powell DW, Kuehn MH, et al. Oxidative stress and the regulation of complement activation in human glaucoma. Invest Ophthalmol Vis Sci. 2010;51(10):5071–82.

    PubMed  PubMed Central  Google Scholar 

  104. Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest. 2011;121(4):1429–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Mirzaei M, Gupta VB, Chick JM, Greco TM, Wu Y, Chitranshi N, et al. Age-related neurodegenerative disease associated pathways identified in retinal and vitreous proteome from human glaucoma eyes. Sci Rep. 2017;7(1):12685.

    PubMed  PubMed Central  Google Scholar 

  106. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Alzheimer's disease. Neurobiol Aging. 2000;21(3):383–421.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Colafrancesco V, Coassin M, Rossi S, Aloe L. Effect of eye NGF administration on two animal models of retinal ganglion cells degeneration. Ann Ist Super Sanita. 2011;47(3):284–9.

    CAS  PubMed  Google Scholar 

  108. Wang H, Wang R, Thrimawithana T, Little PJ, Xu J, Feng ZP, et al. The nerve growth factor signaling and its potential as therapeutic target for glaucoma. Biomed Res Int. 2014;2014:759473.

    PubMed  PubMed Central  Google Scholar 

  109. Popova L, Nuñez M, Nguyen BT, Groth SL, Dennis A, Li Z, Khavari T, Wang SY, Chang R, Fisher AC, Goldberg JL. Recombinant human nerve growth factor (rhNGF) eye drops for glaucoma: interim results. ARVO Annual Meeting Abstract : Invest. Ophthalmol. Vis. Sci. 2018;59(9):1241.

  110. Hood DC, De Moraes CG. Challenges to the common clinical paradigm for diagnosis of glaucomatous damage with OCT and visual fields. Invest Ophthalmol Vis Sci. 2018;59(2):788–91.

    PubMed  PubMed Central  Google Scholar 

  111. Wu Z, Thenappan A, DSD W, Ritch R, Hood DC. Etecting glaucomatous progression with a region-of-interest approach on optical coherence tomography: a signal-to-noise evaluation. Transl Vis Sci Technol. 2018;7(1):19.

    PubMed  PubMed Central  Google Scholar 

  112. Hood DC, Raza AS, de Moraes CGV, Liebmann JM, Ritch R. Glaucomatous damage of the macula. Prog Retin Eye Res. 2013;32:1–21.

    PubMed  Google Scholar 

  113. Fortune B. Optical coherence tomography evaluation of the optic nerve head neuro-retinal rim in glaucoma. Clin Exp Optom. 2018; (published ahead of print). https://doi.org/10.1111/cxo.12833.

  114. Wang B, Nevins JE, Nadler Z, Wollstein G, Ishikawa H, Bilonick RA, et al. In vivo lamina cribrosa micro-architecture in healthy and glaucomatous eyes as assessed by optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54(13):8270–4.

    PubMed  PubMed Central  Google Scholar 

  115. Lee EJ, Kim TW, Kim JA, Kim JA. Parapapillary deep-layer microvasculature dropout in primary open-angle glaucoma eyes with a parapapillary γ-zone. Invest Ophthalmol Vis Sci. 2017;58(13):5673–80.

    PubMed  Google Scholar 

  116. Buckingham BP, Inman DM, Lambert W, Oglesby E, Calkins DJ, Steele MR, et al. Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci. 2008;28(11):2735–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Calkins DJ. Critical pathogenic events underlying progression of neurodegeneration in glaucoma. Prog Retin Eye Res. 2012;31(6):702–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen MF, Chui TY, Alhadeff P, Rosen RB, Ritch R, Dubra A, et al. Adaptive optics imaging of healthy and abnormal regions of retinal nerve fiber bundles of patients with glaucoma. Invest Ophthalmol Vis Sci. 2015;56(1):674–81.

    PubMed  PubMed Central  Google Scholar 

  119. Hood DC, Chen MF, Lee D, Epstein B, Alhadeff P, Rosen RB, et al. Confocal adaptive optics imaging of Peripapillary nerve Fiber bundles: implications for glaucomatous damage seen on Circumpapillary OCT scans. Transl Vis Sci Technol. 2015;4(2):12 eCollection.

    PubMed  PubMed Central  Google Scholar 

  120. Rossi EA, Granger CE, Sharma R, Yang Q, Saito K, Schwarz C, et al. Imaging individual neurons in the retinal ganglion cell layer of the living eye. Proc Natl Acad Sci U S A. 2017;114(3):586–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Liu Z, Kurokawa K, Zhang F, Lee JJ, Miller DT. Imaging and quantifying ganglion cells and other transparent neurons in the living human retina. Proc Natl Acad Sci U S A. 2017;114(48):12803–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Cordeiro MF, Normando EM, Cardoso MJ, Miodragovic S, Jeylani S, Davis BM, et al. Real-time imaging of single neuronal cell apoptosis in patients with glaucoma. Brain. 2017;140(6):1757–67.

    PubMed  PubMed Central  Google Scholar 

  123. Yap ZL, Verma S, Lee YF, Ong C, Mohla A, Perera SA. Glaucoma related retinal oximetry: a technology update. Clin Ophthalmol. 2018;12:79–84.

    PubMed  PubMed Central  Google Scholar 

  124. Shahidi AM, Hudson C, Tayyari F, Flanagan JG. Retinal oxygen saturation in patients with primary open-angle glaucoma using a non-flash Hypespectral camera. Curr Eye Res. 2017;42(4):557–61.

    CAS  PubMed  Google Scholar 

  125. Camp AS, Weinreb RN. Will perimetry be performed to monitor glaucoma in 2025? Ophthalmology. 2017;124(12S):S71–5.

    PubMed  Google Scholar 

  126. De Moraes CG, Hood DC, Thenappan A, Girkin CA, Medeiros FA, Weinreb RN, et al. 24-2 visual fields miss central defects shown on 10-2 tests in Glaucoma suspects, ocular hypertensives, and early Glaucoma. Ophthalmology. 2017;124(10):1449–56.

    PubMed  Google Scholar 

  127. Wu Z, Medeiros FA. Comparison of visual field point-wise event-based and global trend-based analysis for detecting glaucomatous progression. Transl Vis Sci Technol. 2018;7(4):20.

    PubMed  PubMed Central  Google Scholar 

  128. Traynis I, De Moraes CG, Raza AS, Liebmann JM, Ritch R, Hood DC. Prevalence and nature of early glaucomatous defects in the central 10 degrees of the visual field. JAMA Ophthalmol. 2014;132(3):291–7.

    PubMed  PubMed Central  Google Scholar 

  129. Grillo LM, Wang DL, Ramachandran R, Ehrlich AC, De Moraes CG, Ritch R, et al. The 24-2 visual field test misses central macular damage confirmed by the 10-2 visual field test and optical coherence tomography. Transl Vis Sci Technol. 2016;5(2):15.

    PubMed  PubMed Central  Google Scholar 

  130. Wu Z, Medeiros FA, Weinreb RN, Zangwill LM. Performance of the 10-2 and 24-2 visual field tests for detecting central visual field abnormalities in glaucoma. Am J Ophthalmol. 2018;196:10–7.

    PubMed  PubMed Central  Google Scholar 

  131. Viswanathan S, Frishman LJ, Robson JG, Harwerth RS, Smith EL 3rd. The photopic negative response of the macaque electroretinogram: reduction by experimental glaucoma. Invest Ophthalmol Vis Sci. 1999;40(6):1124–36.

    CAS  PubMed  Google Scholar 

  132. Porciatti V. Electrophysiological assessment of retinal ganglion cell function. Exp Eye Res. 2015;141:164–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Wilsey L, Gowrisankaran S, Cull G, Hardin C, Burgoyne CF, Fortune B. Comparing three different modes of electroretinography in experimental glaucoma: diagnostic performance and correlation to structure. Doc Ophthalmol. 2017;134(2):111–28.

    PubMed  PubMed Central  Google Scholar 

  134. Falsini B, Marangoni D, Salgarello T, Stifano G, Montrone L, Campagna F, et al. Structure-function relationship in ocular hypertension and glaucoma: interindividual and interocular analysis by OCT and pattern ERG. Graefes Arch Clin Exp Ophthalmol. 2008;246(8):1153–62.

    PubMed  Google Scholar 

  135. Machida S, Gotoh Y, Toba Y, Ohtaki A, Kaneko M, Kurosaka D. Correlation between photopic negative response and retinal nerve fiber layer thickness and optic disc topography in glaucomatous eyes. Invest Ophthalmol Vis Sci. 2008;49(5):2201–7.

    PubMed  Google Scholar 

  136. Zhang X, Dastiridou A, Francis BA, Tan O, Varma R, Greenfield DS, et al. Comparison of Glaucoma progression detection by optical coherence tomography and visual field. Am J Ophthalmol. 2017;184:63–74.

    PubMed  PubMed Central  Google Scholar 

  137. Vranka JA, Kelley MJ, Acott TS, Keller KE. Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma. Exp Eye Res. 2015;133:112–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Truong TN, Li H, Hong YK, Chen L. Novel characterization and live imaging of Schlemm's canal expressing Prox-1. PLoS One. 2014;9(5):e98245.

    PubMed  PubMed Central  Google Scholar 

  139. Kizhatil K, Gim H, Clark GM, John SW. Sympathetic innervation of the developing aqueous humor drainage structures ARVO Annual Meeting Abstract. Invest Ophthalmol Vis Sci. 2018;59(9):4700.

    Google Scholar 

  140. Khawaja AP, Cooke Bailey JN, Wareham NJ, Scott RA, Simcoe M, Igo RP Jr, et al. UK biobank eye and vision consortium; NEIGHBORHOOD consortium. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet. 2018;50(6):778–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Gao XR, Huang H, Nannini DR, Fan F, Kim H. Genome-wide association analyses identify new loci influencing intraocular pressure. Hum Mol Genet. 2018;27(12):2205–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Borrás T. The pathway from genes to gene therapy in glaucoma: a review of possibilities for using genes as glaucoma drugs. Asia Pac J Ophthalmol (Phila). 2017;6(1):80–93.

    Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

All animal-related procedures were conducted according to protocols approved by Novartis Institutional Animal Care and Use Committee in compliance with Animal Welfare Act regulations and the Guide for the Care and Use of Laboratory Animals and were in adherence to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Authors wish to thank Chenying Guo for mRNA expression data for PTGFR, EP2 and EP4 in rabbit ocular tissues. All authors are employees of Novartis Institutes for Biomedical Research (NIBR) and own Novartis stock. Relevant studies were performed with funding from NIBR.

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Authors and Affiliations

  1. Global Discovery Chemistry, Novartis Institutes for Biomedical Research (NIBR),, Cambridge, Massachusetts, USA

    Christopher M. Adams

  2. Translational Medicine, Ophthalmology, NIBR, Cambridge, Massachusetts, USA

    Rebecca Stacy

  3. Ophthalmology Research, Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts, 02139, USA

    Nalini Rangaswamy, Chad Bigelow, Cynthia L. Grosskreutz & Ganesh Prasanna

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Adams, C.M., Stacy, R., Rangaswamy, N. et al. Glaucoma - Next Generation Therapeutics: Impossible to Possible. Pharm Res 36, 25 (2019). https://doi.org/10.1007/s11095-018-2557-4

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