The Role of Rho Kinase Inhibitors in Corneal Diseases

References

• Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4(1):7. doi:10.1186/1750-1172-4-7
   PubMedGoogle Scholar
• Gomes JAP, Azar DT, Baudouin C, et al. TFOS DEWS II iatrogenic report. Ocul Surf. 2017;15(3):511–538. doi:10.1016/j.jtos.2017.05.004
   PubMed Web of Science ®Google Scholar
• Bowling B. Kanski’s Clinical Ophthalmology. Edinburgh: Elsevier; 2016.
   Google Scholar
• Jeang LJ, Margo CE, Espana EM. Diseases of the corneal endothelium. Exp Eye Res. 2021;205:108495. doi:10.1016/j.exer.2021.108495
   PubMed Web of Science ®Google Scholar
• Rao PV, Pattabiraman PP, Kopczynski C. Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: bench to bedside research. Exp Eye Res. 2017;158:23–32. doi:10.1016/j.exer.2016.08.023
   PubMed Web of Science ®Google Scholar
• Moshirfar M, Parker L, Birdsong OC, et al. Use of Rho kinase inhibitors in ophthalmology: a review of the literature; 2018.
   Google Scholar
• Karri R, Chong EW. ROCK inhibitors in ophthalmology: a critical review of the existing clinical evidence. Clin Experiment Ophthalmol. 2023;ceo.14224. doi:10.1111/ceo.14224
   PubMed Web of Science ®Google Scholar
• Narumiya S, Tanji M, Ishizaki T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev. 2009;28(1–2):65–76. doi:10.1007/s10555-008-9170-7
   PubMed Web of Science ®Google Scholar
• Chen M, Liu A, Ouyang Y, Huang Y, Chao X, Pi R. Fasudil and its analogs: a new powerful weapon in the long war against central nervous system disorders? Expert Opin Investig Drugs. 2013;22(4):537–550. doi:10.1517/13543784.2013.778242
   PubMed Web of Science ®Google Scholar
• Singh IP, Fechtner RD, Myers JS, et al. Pooled efficacy and safety profile of netarsudil ophthalmic solution 0.02% in patients with open-angle glaucoma or ocular hypertension. J Glaucoma. 2020;29(10):878–884. doi:10.1097/IJG.0000000000001634
   PubMed Web of Science ®Google Scholar
• Asrani S, Bacharach J, Holland E, et al. Fixed-dose combination of netarsudil and latanoprost in ocular hypertension and open-angle glaucoma: pooled efficacy/safety analysis of phase 3 MERCURY-1 and −2. Adv Ther. 2020;37(4):1620–1631. doi:10.1007/s12325-020-01277-2
   PubMed Web of Science ®Google Scholar
• Tanihara H, Inoue T, Yamamoto T, et al. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol. 2016;94(1):e26–e34. doi:10.1111/aos.12829
   PubMed Web of Science ®Google Scholar
• Sakata R, Fujishiro T, Saito H, Honjo M, Shirato S, Aihara M. The additive effect of ROCK inhibitor on prostaglandin-treated Japanese patients with glaucoma indicating 15 mmHg and under: ROCK U-15. Adv Ther. 2021;38(7):3760–3770. doi:10.1007/s12325-021-01775-x
   PubMed Web of Science ®Google Scholar
• Luo LJ, Nguyen DD, Lai JY. Harnessing the tunable cavity of nanoceria for enhancing Y-27632-mediated alleviation of ocular hypertension. Theranostics. 2021;11(11):5447–5463. doi:10.7150/thno.54525
   PubMed Web of Science ®Google Scholar
• Okumura N, Okazaki Y, Inoue R, et al. Effect of the rho-associated kinase inhibitor eye drop (Ripasudil) on corneal endothelial wound healing. Invest Opthalmol Vis Sci. 2016;57(3):1284. doi:10.1167/iovs.15-18586
   PubMed Web of Science ®Google Scholar
• Kinoshita S, Koizumi N, Ueno M, et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. N Engl J Med. 2018;378(11):995–1003. doi:10.1056/NEJMoa1712770
   PubMed Web of Science ®Google Scholar
• Kinoshita S, Colby KA, Kruse FE. A close look at the clinical efficacy of rho-associated protein kinase inhibitor eye drops for fuchs endothelial corneal dystrophy. Cornea. 2021;40:1225–1228. doi:10.1097/ICO.0000000000002642
   PubMed Web of Science ®Google Scholar
• Parekh M, Miall A, Deshpande N, Jurkunas UV. Effect of ROCK inhibitor on cell migration in fuchs endothelial corneal dystrophy. Invest Ophthalmol Vis Sci. 2022;63:7.
   Web of Science ®Google Scholar
• Inomata T, Fujimoto K, Okumura Y, et al. Novel immunotherapeutic effects of topically administered ripasudil (K-115) on corneal allograft survival. Sci Rep. 2020;10(1):19817. doi:10.1038/s41598-020-76882-w
   PubMed Web of Science ®Google Scholar
• Kopecny LR, Lee BWH, Coroneo MT. A systematic review on the effects of ROCK inhibitors on proliferation and/or differentiation in human somatic stem cells: a hypothesis that ROCK inhibitors support corneal endothelial healing via acting on the limbal stem cell niche. Ocul Surf. 2023;27:16–29. doi:10.1016/j.jtos.2022.12.008
   PubMed Web of Science ®Google Scholar
• Amano M, Chihara K, Kimura K, et al. Formation of actin stress fibers and focal adhesions enhanced by rho-kinase. Science. 1997;275(5304):1308–1311. doi:10.1126/science.275.5304.1308
   PubMed Web of Science ®Google Scholar
• Maekawa M, Ishizaki T, Boku S, et al. Signaling from rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999;285:895–898. doi:10.1126/science.285.5429.895
   PubMed Web of Science ®Google Scholar
• Totsukawa G, Yamakita Y, Yamashiro S, Hartshorne DJ, Sasaki Y, Matsumura F. Distinct roles of rock (rho-kinase) and mlck in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3t3 fibroblasts. J Cell Biol. 2000;150(4):797–806. doi:10.1083/jcb.150.4.797
   PubMed Web of Science ®Google Scholar
• Nakamura M, Nagano T, Chikama T, Nishida T. Role of the small GTP-binding protein rho in epithelial cell migration in the rabbit cornea. Invest Ophthalmol Visual Sci. 2001;42:5.
   Web of Science ®Google Scholar
• Yin J, Yu FSX. Rho kinases regulate corneal epithelial wound healing. Am J Physiol Cell Physiol. 2008;295:C378–87. doi:10.1152/ajpcell.90624.2007
   PubMed Web of Science ®Google Scholar
• Riento K, Ridley AJ. ROCKs: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003;4(6):446–456. doi:10.1038/nrm1128
   PubMed Web of Science ®Google Scholar
• Leung T, Chen XQ, Manser E, Lim L. The p160 RhoA-Binding Kinase ROK is a member of a kinase family and is involved in the reorganization of the cytoskeleton. MOL CELL BIOL. 1996;16:5313–5327. doi:10.1128/MCB.16.10.5313
   PubMed Web of Science ®Google Scholar
• Katoh K, Kano Y, Noda Y. Rho-associated kinase-dependent contraction of stress fibres and the organization of focal adhesions. J R Soc Interface. 2011;8(56):305–311. doi:10.1098/rsif.2010.0419
   PubMed Web of Science ®Google Scholar
• Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990–994. doi:10.1038/40187
   PubMed Web of Science ®Google Scholar
• Olson MF. Applications for ROCK kinase inhibition. Curr Opin Cell Biol. 2008;20(2):242–248. doi:10.1016/j.ceb.2008.01.002
   PubMed Web of Science ®Google Scholar
• Lin CW, Sherman B, Moore LA, et al. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J Ocul Pharmacol Ther. 2018;34(1–2):40–51. doi:10.1089/jop.2017.0023
   PubMed Web of Science ®Google Scholar
• Kubo T. The therapeutic effects of Rho-ROCK inhibitors on CNS disorders. Ther Clin Risk Manag. 2008;4:605–615. doi:10.2147/TCRM.S2907
   PubMedGoogle Scholar
• Nguyen Dinh Cat A, Callera GE, Friederich-Persson M, et al. Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling. Sci Rep. 2018;8(1):2952. doi:10.1038/s41598-018-21087-5
   PubMedGoogle Scholar
• Rodriguez-Hernandez I, Cantelli G, Bruce F, Sanz-Moreno V. Rho, ROCK and actomyosin contractility in metastasis as drug targets. F1000Research. 2016;5:783. doi:10.12688/f1000research.7909.1
   Google Scholar
• Kimura K, Ito M, Amano M, et al. Regulation of myosin phosphatase by rho and rho-associated kinase (Rho-Kinase). Science. 1996;273:245–248. doi:10.1126/science.273.5272.245
   PubMed Web of Science ®Google Scholar
• Vercammen H, Miron A, Oellerich S, et al. Corneal endothelial wound healing: understanding the regenerative capacity of the innermost layer of the cornea. Transl Res. 2022;248:111–127. doi:10.1016/j.trsl.2022.05.003
   PubMed Web of Science ®Google Scholar
• Okumura N, Koizumi N, Ueno M, et al. The new therapeutic concept of using a rho kinase inhibitor for the treatment of corneal endothelial dysfunction. Cornea. 2011;30(Supplement 1):S54–S59. doi:10.1097/ICO.0b013e3182281ee1
   PubMedGoogle Scholar
• Narumiya S, Ishizaki T, Ufhata M. Use and properties of ROCK-specific inhibitor Y-27632. In: Methods in Enzymology. Elsevier; 2000:273–284. doi:10.1016/S0076-6879(00)25449-9
   Google Scholar
• Syed ZA, Rapuano CJ. Rho kinase (ROCK) inhibitors in the management of corneal endothelial disease. Curr Opin Ophthalmol. 2021;32(3):268–274. doi:10.1097/ICU.0000000000000748
   PubMed Web of Science ®Google Scholar
• Hahmann C, Schroeter T. Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity. Cell Mol Life Sci. 2010;67(2):171–177. doi:10.1007/s00018-009-0189-x
   PubMed Web of Science ®Google Scholar
• Meekins LC, Rosado-Adames N, Maddala R, Zhao JJ, Rao PV, Afshari NA. Corneal endothelial cell migration and proliferation enhanced by rho kinase (ROCK) inhibitors in in vitro and in vivo models. Invest Opthalmol Vis Sci. 2016;57(15):6731. doi:10.1167/iovs.16-20414
   PubMed Web of Science ®Google Scholar
• Okumura N, Ueno M, Koizumi N, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK Inhibitor. Invest Opthalmol Vis Sci. 2009;50(8):3680. doi:10.1167/iovs.08-2634
   PubMed Web of Science ®Google Scholar
• Okumura N, Nakano S, Kay EP, et al. Involvement of Cyclin D and p27 in cell proliferation mediated by ROCK Inhibitors Y-27632 and Y-39983 during corneal endothelium wound healing. Invest Opthalmol Vis Sci. 2014;55(1):318. doi:10.1167/iovs.13-12225
   PubMed Web of Science ®Google Scholar
• Okumura N, Kinoshita S, Koizumi N. Application of rho kinase inhibitors for the treatment of corneal endothelial diseases. J Ophthalmol. 2017;2017:1–8. doi:10.1155/2017/2646904
   Web of Science ®Google Scholar
• Huang MJ, Kane S, Dhaliwal DK. Descemetorhexis without endothelial keratoplasty versus DMEK for treatment of fuchs endothelial corneal dystrophy. Cornea. 2018;37(12):1479–1483. doi:10.1097/ICO.0000000000001742
   PubMed Web of Science ®Google Scholar
• Davies E, Jurkunas U, Pineda R. Pilot study of corneal clearance with the use of a rho-kinase inhibitor after descemetorhexis without endothelial keratoplasty for fuchs endothelial corneal dystrophy. Cornea. 2021;40(7):899–902. doi:10.1097/ICO.0000000000002691
   PubMed Web of Science ®Google Scholar
• Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Opthalmol Vis Sci. 2013;54(4):2493. doi:10.1167/iovs.12-11320
   PubMed Web of Science ®Google Scholar
• Pakravan M, Beni AN, Ghahari E, et al. The ocular hypotensive efficacy of topical fasudil, a rho-associated protein kinase inhibitor, in patients with end-stage glaucoma. Am J Ther. 2017;24(6):e676–e680. doi:10.1097/MJT.0000000000000362
   PubMed Web of Science ®Google Scholar
• Drugbank. Y-27632. Available from: https://go.drugbank.com/drugs/DB08756. Accessed December 12, 2023.
   Google Scholar
• Fasudil. In: Wikipedia; 2023. Available from: https://commons.wikimedia.org/wiki/File:Fasudil.svg. Accessed December 12, 2023.
   Google Scholar
• Drugbank. Ripasudil. Available from: https://go.drugbank.com/drugs/DB13165. Accessed December 12, 2023.
   Google Scholar
• Drugbank. Netarsudil. Available from: https://go.drugbank.com/drugs/DB13931. Accessed December 12, 2023.
   Google Scholar
• Ishizaki T, Uehata M, Tamechika I, et al. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol. 2000;57:976–983.
   PubMed Web of Science ®Google Scholar
• Defert O, Boland S. Rho kinase inhibitors: a patent review (2014 – 2016). Expert Opin Ther Pat. 2017;27(4):507–515. doi:10.1080/13543776.2017.1272579
   PubMed Web of Science ®Google Scholar
• Li G, Mukherjee D, Navarro I, et al. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur J Pharmacol. 2016;787:20–31. doi:10.1016/j.ejphar.2016.04.002
   PubMed Web of Science ®Google Scholar
• Li M, Huang Y, Ma AAK, Lin E, Diamond MI. Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol Dis. 2009;36(3):413–420. doi:10.1016/j.nbd.2009.06.011
   PubMed Web of Science ®Google Scholar
• Ahmadieh H, Nourinia R, Hafezi-Moghadam A, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: a pilot randomised clinical trial. Br J Ophthalmol. 2019;103(7):922–927. doi:10.1136/bjophthalmol-2018-312244
   PubMed Web of Science ®Google Scholar
• Mietzner R, Kade C, Froemel F, et al. Fasudil loaded PLGA microspheres as potential intravitreal depot formulation for glaucoma therapy. Pharmaceutics. 2020;12(8):706. doi:10.3390/pharmaceutics12080706
   PubMed Web of Science ®Google Scholar
• Chen H, Lin Y, Han M, Bai S, Wen S. Simultaneous quantitative analysis of fasudil and its active metabolite in human plasma by liquid chromatography electro-spray tandem mass spectrometry. J Pharm Biomed Anal. 2010;52(2):242–248. doi:10.1016/j.jpba.2009.12.028
   PubMed Web of Science ®Google Scholar
• Garnock-Jones KP. Ripasudil: first Global Approval. Drugs. 2014;74(18):2211–2215. doi:10.1007/s40265-014-0333-2
   PubMed Web of Science ®Google Scholar
• Tanihara H, Inoue T, Yamamoto T, et al. Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study. Acta Ophthalmol. 2015;93(4):e254–e260. doi:10.1111/aos.12599
   PubMed Web of Science ®Google Scholar
• Tanihara H, Inoue T, Yamamoto T, et al. Additive intraocular pressure–lowering effects of the rho kinase inhibitor ripasudil (K-115) Combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol. 2015;133(7):755. doi:10.1001/jamaophthalmol.2015.0525
   PubMed Web of Science ®Google Scholar
• Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Araie M. Phase 2 randomized clinical study of a rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol. 2013;156(4):731–736.e2. doi:10.1016/j.ajo.2013.05.016
   PubMed Web of Science ®Google Scholar
• Moura-Coelho N, Tavares Ferreira J, Bruxelas CP, Dutra-Medeiros M, Cunha JP, Pinto Proença R. Rho kinase inhibitors—a review on the physiology and clinical use in Ophthalmology. Graefes Arch Clin Exp Ophthalmol. 2019;257(6):1101–1117. doi:10.1007/s00417-019-04283-5
   PubMed Web of Science ®Google Scholar
• Kaneko Y, Ohta M, Inoue T, et al. Effects of K-115 (Ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm’s canal endothelial cells. Sci Rep. 2016;6(1):19640. doi:10.1038/srep19640
   PubMed Web of Science ®Google Scholar
• Inoue T, Tanihara H. Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma. Expert Opin Pharmacother. 2017;18(15):1669–1673. doi:10.1080/14656566.2017.1378344
   PubMed Web of Science ®Google Scholar
• 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):51–54. doi:10.1097/IJG.0b013e3182952213
   PubMed Web of Science ®Google Scholar
• Okumura N, Koizumi N, Ueno M, et al. ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. Am J Pathol. 2012;181(1):268–277. doi:10.1016/j.ajpath.2012.03.033
   PubMed Web of Science ®Google Scholar
• Moloney G, Garcerant Congote D, Hirnschall N, et al. Descemet stripping only supplemented with topical ripasudil for Fuchs endothelial dystrophy 12-month outcomes of the Sydney Eye Hospital Study. Cornea. 2021;40(3):320–326. doi:10.1097/ICO.0000000000002437
   PubMed Web of Science ®Google Scholar
• Macsai MS, Shiloach M. Use of topical rho kinase inhibitors in the treatment of fuchs dystrophy after descemet stripping only. Cornea. 2019;38(5):529–534. doi:10.1097/ICO.0000000000001883
   PubMed Web of Science ®Google Scholar
• Price MO, Price FW. Randomized, double-masked, pilot study of netarsudil 0.02% ophthalmic solution for treatment of corneal edema in fuchs dystrophy. Am J Ophthalmol. 2021;227:100–105. doi:10.1016/j.ajo.2021.03.006
   PubMedGoogle Scholar
• Zeng P, Biao PR, Li P, et al. Fasudil hydrochloride, a potent ROCK inhibitor, inhibits corneal neovascularization after alkali burns in mice. Mol Vis. 2015;21:1.
   PubMed Web of Science ®Google Scholar
• Davies E. Case series: novel utilization of rho-kinase inhibitor for the treatment of corneal edema. Cornea. 2021;40(1):116–120. doi:10.1097/ICO.0000000000002421
   PubMed Web of Science ®Google Scholar
• Moshirfar M, Somani AN, Vaidyanathan U, Patel BC. Fuchs Endothelial Dystrophy. StatPearls. StatPearls Publishing; 2023. Available from. http://www.ncbi.nlm.nih.gov/books/NBK545248/. Accessed June 28, 2023.
   Google Scholar
• Price MO, Mehta JS, Jurkunas UV, Price FW. Corneal endothelial dysfunction: evolving understanding and treatment options. Prog Retin Eye Res. 2021;82:100904. doi:10.1016/j.preteyeres.2020.100904
   PubMed Web of Science ®Google Scholar
• Jurkunas UV. Fuchs endothelial corneal dystrophy through the prism of oxidative stress. Cornea. 2018;37:S50. doi:10.1097/ICO.0000000000001775
   PubMed Web of Science ®Google Scholar
• Chow SC, Chan JCH. Review on the use of topical ocular hypertonic saline in corneal edema. Cornea. 2021;40(4):533. doi:10.1097/ICO.0000000000002652
   PubMed Web of Science ®Google Scholar
• Blitzer AL, Colby KA. Update on the surgical management of fuchs endothelial corneal dystrophy. Ophthalmol Ther. 2020;9(4):757–765. doi:10.1007/s40123-020-00293-3
   PubMed Web of Science ®Google Scholar
• Feizi S. Corneal endothelial cell dysfunction: etiologies and management. Ther Adv Ophthalmol. 2018;10:2515841418815802. doi:10.1177/2515841418815802
   Web of Science ®Google Scholar
• Feinbaum C. New treatment reduces corneal oedema after cataract surgery. Ophthalmology Times; 2015. Available from: https://www.ophthalmologytimes.com/view/ote-new-treatment-reduces-corneal-oedema-after-cataract-surgery. Accessed June 29, 2023.
   Google Scholar
• Gonçalves ED, Campos M, Paris F, Gomes JÁP, de Farias CC. Ceratopatia bolhosa: etiopatogênese e tratamento. Arq Bras Oftalmol. 2008;71:61–64. doi:10.1590/S0004-27492008000700012
   PubMedGoogle Scholar
• Antonini M, Coassin M, Gaudenzi D, Di Zazzo A. Rho-associated kinase inhibitor eye drops in challenging cataract surgery. Am J Ophthalmol Case Rep. 2022;25:101245. doi:10.1016/j.ajoc.2021.101245
   PubMedGoogle Scholar
• Chang JH, Gabison EE, Kato T, Azar DT. Corneal neovascularization. Curr Opin Ophthalmol. 2001;12(4):242–249. doi:10.1097/00055735-200108000-00002
   PubMed Web of Science ®Google Scholar
• Sijnave D, Van Bergen T, Castermans K, et al. Inhibition of rho-associated kinase prevents pathological wound healing and neovascularization after corneal Trauma. Cornea. 2015;34(9):1120–1129. doi:10.1097/ICO.0000000000000493
   PubMed Web of Science ®Google Scholar
• Silva L, Najafi A, Suwan Y, Teekhasaenee C, Ritch R. The iridocorneal endothelial syndrome. Surv Ophthalmol. 2018;63(5):665–676. doi:10.1016/j.survophthal.2018.01.001
   PubMed Web of Science ®Google Scholar
• Saito H, Kagami S, Mishima K, Mataki N, Fukushima A, Araie M. Long-term side effects including blepharitis leading to discontinuation of ripasudil. J Glaucoma. 2019;28(4):289–293. doi:10.1097/IJG.0000000000001203
   PubMed Web of Science ®Google Scholar
• Maruyama Y, Ikeda Y, Mori K, et al. Safety and efficacy of long-term ripasudil 0.4% instillation for the reduction of intraocular pressure in Japanese open-angle glaucoma patients. J Ocul Pharmacol Ther. 2020;36(4):229–233. doi:10.1089/jop.2019.0125
   PubMed Web of Science ®Google Scholar
• Serle JB, Katz LJ, McLaurin E, 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;186:116–127. doi:10.1016/j.ajo.2017.11.019
   PubMed Web of Science ®Google Scholar
• Khouri AS, Serle JB, Bacharach J, et al. Once-daily netarsudil versus twice-daily timolol in patients with elevated intraocular pressure: the randomized phase 3 ROCKET-4 study. Am J Ophthalmol. 2019;204:97–104. doi:10.1016/j.ajo.2019.03.002
   PubMed Web of Science ®Google Scholar
• Bhargava M, Sen S, Bhambhani V, Paul R, Dutta C. Reticular epithelial corneal edema as a novel side-effect of rho kinase inhibitors: an Indian scenario. Indian J Ophthalmol. 2022;70(4):1163. doi:10.4103/ijo.IJO_2865_21
   PubMed Web of Science ®Google Scholar
• Wisely CE, Liu KC, Gupta D, Carlson AN, Asrani SG, Kim T. Reticular bullous epithelial edema in corneas treated with netarsudil: a case series. Am J Ophthalmol. 2020;217:20–26. doi:10.1016/j.ajo.2020.04.002
   PubMed Web of Science ®Google Scholar
• Soh YQ, Peh G, George BL, et al. Predicative factors for corneal endothelial cell migration. Invest Ophthalmol Vis Sci. 2016;57(2):338–348. doi:10.1167/iovs.15-18300
   PubMed Web of Science ®Google Scholar
• Amador C, Shah R, Ghiam S, Kramerov AA, Ljubimov AV. Gene therapy in the anterior eye segment. Curr Gene Ther. 2022;22(2):104–131. doi:10.2174/1566523221666210423084233
   PubMed Web of Science ®Google Scholar
• Mehta JS, Kocaba V, Soh YQ. The future of keratoplasty: cell-based therapy, regenerative medicine, bioengineering keratoplasty, gene therapy. Curr Opin Ophthalmol. 2019;30(4):286–291. doi:10.1097/ICU.0000000000000573
   PubMed Web of Science ®Google Scholar
• Zarouchlioti C, Sanchez-Pintado B, Hafford Tear NJ, et al. Antisense therapy for a common corneal dystrophy ameliorates TCF4 repeat expansion-mediated toxicity. Am J Hum Genet. 2018;102(4):528–539. doi:10.1016/j.ajhg.2018.02.010
   PubMed Web of Science ®Google Scholar
• Hu J, Rong Z, Gong X, et al. Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs’ dystrophy. Hum Mol Genet. 2018;27(6):1015–1026. doi:10.1093/hmg/ddy018
   PubMed Web of Science ®Google Scholar
• Pinto BS, Saxena T, Oliveira R, et al. Impeding transcription of expanded microsatellite repeats by deactivated cas9. Mol Cell. 2017;68(3):479–490.e5. doi:10.1016/j.molcel.2017.09.033
   PubMed Web of Science ®Google Scholar
• Rong Z, Gong X, Hulleman JD, Corey DR, Mootha VV. Trinucleotide repeat-targeting dCas9 as a therapeutic strategy for fuchs’ endothelial corneal dystrophy. Transl Vis Sci Technol. 2020;9(9):47. doi:10.1167/tvst.9.9.47
   PubMed Web of Science ®Google Scholar
• Peh GSL, Ang HP, Lwin CN, et al. Regulatory compliant tissue-engineered human corneal endothelial grafts restore corneal function of rabbits with bullous keratopathy. Sci Rep. 2017;7(1):14149. doi:10.1038/s41598-017-14723-z
   PubMed Web of Science ®Google Scholar
• Koizumi N, Sakamoto Y, Okumura N, et al. Cultivated corneal endothelial cell sheet transplantation in a primate model. Invest Opthalmol Vis Sci. 2007;48(10):4519. doi:10.1167/iovs.07-0567
   PubMed Web of Science ®Google Scholar