Animal models of Dry Eye Disease: Application to Drug Discovery

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Fatima Khwaja Robert A. Honkanen Basil Rigas


Dry eye disease (DED), a multifactorial disorder of the ocular surface and tear film, affects 5-50% of the global population. Currently, no satisfactory treatments of DED exist. Ongoing efforts to identify novel therapeutic agents are handicapped by the limitations of its preclinical animal models, which to some extent reflect the pathophysiological complexities of DED..  A plethora of DED models employing multiple animal species (mice, rats, cats, rabbits, dogs, and non-human primates) has been reported, each aiming to capture components of DED that appear to determine its pathophysiology and response to novel treatments. Here, we review the main animal models of DED and attempt to place each in the context of drug discovery. We also discuss a nascent method for ex vivo culture of human conjunctival cells that may abbreviate early screening of candidate therapeutics. Despite the remaining challenges, there is justified optimism that with the contribution of these preclinical models, the development of an efficacious and safe treatment of DED will be forthcoming.

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KHWAJA, Fatima; HONKANEN, Robert A.; RIGAS, Basil. Animal models of Dry Eye Disease: Application to Drug Discovery. Medical Research Archives, [S.l.], v. 12, n. 3, mar. 2024. ISSN 2375-1924. Available at: <>. Date accessed: 13 apr. 2024. doi:
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Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276-283. Doi:10.1016/j.jtos.2017.05.008.
2. Mondal H, Kim HJ, Mohanto N, Jee JP. A Review on Dry Eye Disease Treatment: Recent Progress, Diagnostics, and Future Perspectives. Pharmaceutics. 2023;15(3). Doi:10.3390/pharmaceutics15030990.
3. Clayton JA. Dry Eye. New England Journal of Medicine. 2018;378(23):2212-2223. Doi:10.1056/NEJMra1407936.
4. Gillan, W.D.H. Tear biochemistry: A review. S Afr Optom. 2010;69(2):100-106.
5. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II Epidemiology Report. Ocul Surf. 2017;15(3):334-365. Doi:10.1016/j.jtos.2017.05.003.
6. Bielory L, Syed BA. Pharmacoeconomics of anterior ocular inflammatory disease. Curr Opin Allergy Clin Immunol. 2013;13(5):537-542. Doi:10.1097/ACI.0b013e328364d843.
7. Huang W, Tourmouzis K, Perry H, Honkanen RA, Rigas B. Animal models of dry eye disease: Useful, varied and evolving (Review). Exp Ther Med. 2021;22(6):1394. Doi:10.3892/etm.2021.10830.
8. Zhan Q, Zhang J, Lin Y, Chen W, Fan X, Zhang D. Pathogenesis and treatment of Sjogren's syndrome: Review and update. Front Immunol. 2023;14:1127417. Doi:10.3389/fimmu.2023.1127417.
9. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992;356(6367):314-317. Doi:10.1038/356314a0.
10. Singer GG, Abbas AK. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994;1(5):365-371. Doi:10.1016/1074-7613(94)90067-1.
11. Törnwall J, Lane TE, Fox RI, Fox HS. T cell attractant chemokine expression initiates lacrimal gland destruction in nonobese diabetic mice. Lab Invest. 1999;79(12):1719-1726.
12. Robinson CP, Cornelius J, Bounous DE, Yamamoto H, Humphreys-Beher MG, Peck AB. Characterization of the changing lymphocyte populations and cytokine expression in the exocrine tissues of autoimmune NOD mice. Autoimmunity. 1998;27(1):29-44. Doi:10.3109/08916939809008035.
13. Yamamoto H, Sims NE, Macauley SP, Nguyen KH, Nakagawa Y, Humphreys-Beher MG. Alterations in the secretory response of non-obese diabetic (NOD) mice to muscarinic receptor stimulation. Clin Immunol Immunopathol. 1996;78(3):245-255. Doi:10.1006/clin.1996.0036.
14. Park YS, Gauna AE, Cha S. Mouse Models of Primary Sjogren's Syndrome. Curr Pharm Des. 2015;21(18):2350-2364. Doi:10.2174/1381612821666150316120024.
15. Dursun D, Wang M, Monroy D, et al. A mouse model of keratoconjunctivitis sicca. Investigative ophthalmology & visual science. 2002;43(3):632-638.
16. Schrader S, Mircheff AK, Geerling G. Animal models of dry eye. Dev Ophthalmol. 2008;41:298-312. Doi:10.1159/000131097.
17. Stewart P, Chen Z, Farley W, Olmos L, Pflugfelder SC. Effect of experimental dry eye on tear sodium concentration in the mouse. Eye Contact Lens. 2005;31(4):175-178. Doi:10.1097/01.icl.0000161705.19602.c9.
18. Yeh S, Song XJ, Farley W, Li D-Q, Stern ME, Pflugfelder SC. Apoptosis of Ocular Surface Cells in Experimentally Induced Dry Eye. Invest Ophthalmol Vis Sci. 2003;44(1):124-129. Doi:10.1167/iovs.02-0581.
19. Niederkorn JY, Stern ME, Pflugfelder SC, et al. Desiccating stress induces T cell-mediated Sjogren's syndrome-like lacrimal keratoconjunctivitis. Journal of Immunology. 2006;176(7):3950-3957. Doi:10.4049/jimmunol.176.7.3950.
20. Barabino S, Shen L, Chen L, Rashid S, Rolando M, Dana MR. The controlled-environment chamber: a new mouse model of dry eye. Invest Ophthalmol Vis Sci. 2005;46(8):2766-2771. Doi:10.1167/iovs.04-1326.
21. Shinomiya K, Ueta M, Kinoshita S. A new dry eye mouse model produced by exorbital and intraorbital lacrimal gland excision. Sci Rep. 2018;8(1):1483. Doi:10.1038/s41598-018-19578-6.
22. Nagata M, Nakamura T, Hata Y, Yamaguchi S, Kaku T, Kinoshita S. JBP485 promotes corneal epithelial wound healing. Sci Rep. 2015;5:14776. Doi:10.1038/srep14776.
23. Remtulla S, Hallett PE. A schematic eye for the mouse, and comparisons with the rat. Vision Res. 1985;25(1):21-31.
24. Parihar JK, Jain VK, Chaturvedi P, Kaushik J, Jain G, Parihar AK. Computer and visual display terminals (VDT) vision syndrome (CVDTS). Med J Armed Forces India. 2016;72(3):270-276. Doi:10.1016/j.mjafi.2016.03.016.
25. Ye Z, Abe Y, Kusano Y, et al. The influence of visual display terminal use on the physical and mental conditions of administrative staff in Japan. J Physiol Anthropol. 2007;26(2):69-73. Doi:10.2114/jpa2.26.69.
26. Fjaervoll K, Fjaervoll H, Magno M, et al. Review on the possible pathophysiological mechanisms underlying visual display terminal-associated dry eye disease. Acta Ophthalmol. 2022;100(8):861-877. Doi:10.1111/aos.15150.
27. Nakamura S, Kinoshita S, Yokoi N, et al. Lacrimal hypofunction as a new mechanism of dry eye in visual display terminal users. PLoS One. 2010;5(6):e11119. Doi:10.1371/journal.pone.0011119.
28. Viau S, Maire MA, Pasquis B, et al. Time course of ocular surface and lacrimal gland changes in a new scopolamine-induced dry eye model. Graefes Arch Clin Exp Ophthalmol. 2008;246(6):857-867. Doi:10.1007/s00417-008-0784-9.
29. Yoon S, Han S, Jeon KJ, Kwon S. Effects of collected road dusts on cell viability, inflammatory response, and oxidative stress in cultured human corneal epithelial cells. Toxicol Lett. 2018;284:152-160. Doi:10.1016/j.toxlet.2017.12.012.
30. Mu N, Wang H, Chen D, et al. A Novel Rat Model of Dry Eye Induced by Aerosol Exposure of Particulate Matter. Invest Ophthalmol Vis Sci. 2022;63(1):39. Doi:10.1167/iovs.63.1.39.
31. Hisey EA, Galor A, Leonard BC. A comparative review of evaporative dry eye disease and meibomian gland dysfunction in dogs and humans. Vet Ophthalmol. 2023;26 Suppl 1(Suppl 1):16-30. Doi:10.1111/vop.13066.
32. Gao J, Schwalb TA, Addeo JV, Ghosn CR, Stern ME. The role of apoptosis in the pathogenesis of canine keratoconjunctivitis sicca: the effect of topical Cyclosporin A therapy. Cornea. 1998;17(6):654-663. Doi:10.1097/00003226-199811000-00014.
33. Barabino S, Dana MR. Animal models of dry eye: a critical assessment of opportunities and limitations. Invest Ophthalmol Vis Sci. 2004;45(6):1641-1646. Published 2004/05/27.
34. Stiles J, Kimmitt B. Eye examination in the cat: Step-by-step approach and common findings. J Feline Med Surg. 2016;18(9):702-711. Doi:10.1177/1098612x16660444.
35. Helper LC, Magrane WG, Koehm J, Johnson R. Surgical induction of keratoconjunctivitis sicca in the dog. Journal of the American Veterinary Medical Association. 1974;165(2):172-174.
36. Maitchouk DY, Beuerman RW, Ohta T, Stern M, Varnell RJ. Tear production after unilateral removal of the main lacrimal gland in squirrel monkeys. Archives of ophthalmology (Chicago, Ill : 1960). 2000;118(2):246-252.
37. Gong L, Guan Y, Cho W, et al. A new non-human primate model of desiccating stress-induced dry eye disease. Sci Rep. 2022;12(1):7957. Doi:10.1038/s41598-022-12009-7.
38. Schechter JE, Warren DW, Mircheff AK. A lacrimal gland is a lacrimal gland, but rodent's and rabbit's are not human. Ocul Surf. 2010;8(3):111-134.
39. Miyake H, Oda T, Katsuta O, Seno M, Nakamura M. A Novel Model of Meibomian Gland Dysfunction Induced with Complete Freund's Adjuvant in Rabbits. Vision (Basel). 2017;1(1). Doi:10.3390/vision1010010
40. Gilbard JP, Rossi SR, Heyda KG. Tear film and ocular surface changes after closure of the meibomian gland orifices in the rabbit. Ophthalmology. 1989;96(8):1180-1186.
41. Fujihara T, Nagano T, Nakamura M, Shirasawa E. Establishment of a rabbit short-term dry eye model. J Ocul Pharmacol Ther. 1995;11(4):503-508. Doi:10.1089/jop.1995.11.503.
42. Nagelhout TJ, Gamache DA, Roberts L, Brady MT, Yanni JM. Preservation of tear film integrity and inhibition of corneal injury by dexamethasone in a rabbit model of lacrimal gland inflammation-induced dry eye. J Ocul Pharmacol Ther. 2005;21(2):139-148. Doi:10.1089/jop.2005.21.139.
43. Honkanen R, Nemesure B, Huang L, Rigas B. Diagnosis of Dry Eye Disease Using Principal Component Analysis: A Study in Animal Models of the Disease. Curr Eye Res. 2021;46(5):622-629. Doi:10.1080/02713683.2020.1830115.
44. Huang L, Mackenzie G, Ouyang N, et al. The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats. Br J Pharmacol. 2011;162(7):1521-1533. Doi:10.1111/j.1476-5381.2010.01162.x.
45. Mattheolabakis G, Mackenzie GG, Huang L, Ouyang N, Cheng KW, Rigas B. Topically applied phospho-sulindac hydrogel is efficacious and safe in the treatment of experimental arthritis in rats. Pharm Res. 2013;30(6):1471-1482. Doi:10.1007/s11095-012-0953-8.
46. Honkanen RA, Huang L, Huang W, Rigas B. Establishment of a severe dry eye model using complete dacryoadenectomy in rabbits. J Vis Exp.:Jove 2020; Jan(155). Doi:10.3791/60126.
47. Honkanen RA, Huang L, Xie G, Rigas B. Phosphosulindac is efficacious in an improved concanavalin A-based rabbit model of chronic dry eye disease. Transl Res. 2018;198:58-72. Doi:10.1016/j.trsl.2018.04.002.
48. Honkanen R, Huang W, Huang L, Kaplowitz K, Weissbart S, Rigas B. A New Rabbit Model of Chronic Dry Eye Disease Induced by Complete Surgical Dacryoadenectomy. Curr Eye Res. 2019;44(8):863-872. Doi:10.1080/02713683.2019.1594933.
49. Abdi H, Williams LJ. Principal components analysis. Wiley Interdiscip Rev Comput Stat. 2010;2:433-450.
50. Giuliani A. The application of principal component analysis to drug discovery and biomedical data. Drug Discov Today. 2017;22(7):1069-1076. Doi:10.1016/j.drudis.2017.01.005.
51. Wong CC, Cheng K-C, Rigas B. Preclinical predictors of anticancer drug efficacy: Critical assessment with emphasis on whether nanomolar potency should be required of candidate agents. J Pharm Exp Ther. 2012;in press. J Pharmacol Exp Ther. 2012;341(3):572-578. Doi: 10.1124/jpet.112.191957.
52. Richter M, Piwocka O, Musielak M, Piotrowski I, Suchorska WM, Trzeciak T. From Donor to the Lab: A Fascinating Journey of Primary Cell Lines. Front Cell Dev Biol. 2021;9:711381. Doi:10.3389/fcell.2021.711381.
53. Master A, Huang W, Huang L, et al. Simplified ex-vivo drug evaluation in ocular surface cells: Culture on cellulose filters of cells obtained by impression cytology. Exp Eye Res. 2021;213:108827. Doi:10.1016/j.exer.2021.108827.
54. Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Archives of ophthalmology (Chicago, Ill : 1960). 2012;130(1):90-100. Doi:10.1001/archophthalmol.2011.364.
55. Dana R, Bradley JL, Guerin A, et al. Estimated Prevalence and Incidence of Dry Eye Disease Based on Coding Analysis of a Large, All-age United States Health Care System. Am J Ophthalmol. 2019;202:47-54. Doi:10.1016/j.ajo.2019.01.026.
56. Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea. 2011;30(4):379-387. Doi:10.1097/ICO.0b013e3181f7f363.
57. Baudouin C, Messmer EM, Aragona P, et al. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100(3):300-306. Doi:10.1136/bjophthalmol-2015-307415.
58. Master A, Kontzias A, Huang L, et al. The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye. PLoS One. 2021;16(7):e0254036. Doi:10.1371/journal.pone.0254036.
59. Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022;12(7):3049-3062. Doi:10.1016/j.apsb.2022.02.002.