Modeling the atrophy of retinal pigment epithelium

Purpose: to develop easy-to make and reproducible models of retinal pigment epithelium atrophy (RPE) and retinal degeneration using two types of solution (0.9 % sodium chloride and bevacizumab) and to evaluate these models using clinical instrumental and pathomorphological studies. Material and methods. To create the two models, we used 60 New Zealand albino rabbits divided into 2 groups of 30 animals each (30 eyes). In group 1, 0.01 ml of 0.9 % sodium chloride solution was delivered into the subretinal space at a distance of 1–1.5 mm downwards from the optic disc forming a subretinal bladder, whilst group 2 received 0.01 ml of bevacizumab solution which contained 0.025 mg of the drug. Optical coherence tomography (OCT) and fundus autofluorescence imaging were performed in live rabbits’ eyes before and after the procedure on the 2nd, 7th, 14th, 24th, and 30th day using Heidelberg Spectralis™ SD-OCT (Heidelberg Engineering, Germany). The enucleated eyes were histologically evaluated 14 and 30 days after RPE atrophy modeling. Results. Two easily reproducible experimental models of RPE atrophy have been developed. Clinical and morphological indications of RPE atrophy are described. Histological analysis revealed a more aggressive action of 0.9% sodium chloride solution on the retina and the choroid as compared with the model obtained with a similarly delivered subretinal angiogenesis inhibitor. Conclusion. The obtained experimental models may be useful in investigating various types of RPE atrophy, including those arising from the use of angiogenesis inhibitors.

retinal pigment epithelium atrophy, 0.9 % sodium chloride solution, bevacizumab, inhibitors of angiogenesis

1. M'Barek B. K., Habeler W., Monville C. Stem cell-based RPE therapy for retinal diseases: engineering 3D tissues amenable for regenerative medicine. Adv. Exp. Med. Biol. 2018; 1074: 625–62. doi:10.1007/978-3-319-75402-4_76

2. Gazizova I.R., Alekseev V.N., Nikitin D.N. Experimental reproduction of the glaucomatous process. Oftal'mologicheskie vedomosti. 2013; 6 (3): 43–50 (in Russian).

3. Petters R.M., Alexander C.A., Wells K.D., et al. Genetically engineered large animal model for studying cone photoreceptor survival and degeneration in retinitis pigmentosa. Nat. Biotechnol. 1997; 15 (10): 965–70. doi: 10.1038/nbt1097-965

4. Chader G.J. Animal models in research on retinal degenerations: past progress and future hope. Vision Res. 2002; 42 (4): 393–9. doi: 10.1016/s00426989(01)00212-7

5. Kijas J.W., Cideciyan A.V., Aleman T.S., et al. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc. Natl. Acad. Sci. USA. 2002; 99 (9): 6328–33. doi:10.1073/pnas.082714499

6. Sheremet N.L., Mikaelyan A.A., Andreev A.Yu., et al. Experimental damage of retinal pigment epithelium. Sovremennye tekhnologii v oftal'mologii. 2019; 3: 215–7 (in Russian). https://doi.org/10.25276/2312-4911-2019-3-215-217

7. Bhutto I.A., Ogura S., Baldeosingh R., et al. An acute injury model for the phenotypic characteristics of geographic atrophy. Invest. Ophthalmol. Vis. Sci. 2018; 59 (4): AMD143–AMD151. doi:10.1167/iovs.18-24245

8. Petrus-Reurer S., Bartuma H., Aronsson M., et al. Integration of subretinal suspension transplants of human embryonic stem cell-derived retinal pigment epithelial cells in a large-eyed model of geographic atrophy. Invest. Ophthalmol. Vis. Sci. 2017; 58 (2): 1314–22. doi:10.1167/iovs.16-20738

9. Mones J., Leiva M., Pena T., et al. A swine model of selective geographic atrophy of outer retinal layers mimicking atrophic AMD: a phase I escalating dose of subretinal sodium iodate. Invest. Ophthalmol. Vis. Sci. 2016; 57 (10): 3974–83. doi:10.1167/iovs.16-19355

10. Martin D.F., Maguire M.G., Fine S.L., et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012; 119 (7): 1388–98. doi: https://doi.org/10.1016/j.ophtha.2012.03.053

11. Edelhauser H.F., Van Horn D.L., Hyindiuk R.A., et al. Intraocular irrigating solutions: their effect on the corneal endothelium. Arch. Ophthalmol. 1975; 93 (8): 648–57. doi:10.1001/archopht.1975.01010020614011

12. Merrill D.L., Fleming T.C., Girard L.J. The effects of physiologic balanced salt solutions and normal saline on intraocular and extraocular tissues. Am. Journ. of Ophthalmol. 1960; 49 (5): 895–8. https://doi.org/10.1016/00029394(60)91806-7

13. Breebaart A. C., Nuyts R. M., Pels E., et al. Toxic endothelial cell destruction of the cornea after routine extracapsular cataract surgery. Arch. of Ophthalmol. 1990; 108 (8): 1121–5. doi:10.1001/archopht.1990.01070100077038

14. Anisimova S.Yu., Zagrebel'naya L.V. Intraocular irrigation solutions: a comparative study of BSS and BSS Plus. 2010; 1 (1): 45–9 (in Russian).

15. Muraoka Y., Ikeda H.O., Nakano N., et al. Real-time imaging of rabbit retina with retinal degeneration by using spectral-domain optical coherence tomography. PLoS One. 2012; 7 (4): e36135. doi:10.1371/journal.pone.0036135

16. Famiglietti E.V., Sharpe S.J. Regional topography of rod and immunocytochemically characterized “blue” and “green” cone photoreceptors in rabbit retina. Vis. Neurosci. 1995; 12 (6): 1151–75. doi:10.1017/s0952523800006799

17. Neroeva N.V., Neroev V.V., Katargina L.A., et al. The method of modeling of atrophy of retinal pigment epithelium. Patent RF № 2709247; 2019 (in Russian).

18. Neroeva N.V., Neroev V.V., Zueva M.V., et al. The method of modeling of atrophy of retinal pigment epithelium. Patent RF № 2727000; 2020 (in Russian).