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      Recent advances in genetically modified animal models of glaucoma and their roles in drug repositioning

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          Abstract

          Glaucoma is one of the leading causes of vision loss in the world. Currently, pharmacological intervention for glaucoma therapy is limited to eye drops that reduce intraocular pressure (IOP). Recent studies have shown that various factors as well as IOP are involved in the pathogenesis of glaucoma, especially in the subtype of normal tension glaucoma. To date, various animal models of glaucoma have been established, including glutamate/aspartate transporter knockout (KO) mice, excitatory amino acid carrier 1 KO mice, optineurin E50K knock-in mice, DBA/2J mice and experimentally induced models. These animal models are very useful for elucidating the pathogenesis of glaucoma and for identifying potential therapeutic targets. However, each model represents only some aspects of glaucoma, never the whole disease. This review will summarise the benefits and limitations of using disease models of glaucoma and recent basic research in retinal protection using existing drugs.

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          Most cited references84

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          Global data on visual impairment in the year 2002.

          This paper presents estimates of the prevalence of visual impairment and its causes in 2002, based on the best available evidence derived from recent studies. Estimates were determined from data on low vision and blindness as defined in the International statistical classification of diseases, injuries and causes of death, 10th revision. The number of people with visual impairment worldwide in 2002 was in excess of 161 million, of whom about 37 million were blind. The burden of visual impairment is not distributed uniformly throughout the world: the least developed regions carry the largest share. Visual impairment is also unequally distributed across age groups, being largely confined to adults 50 years of age and older. A distribution imbalance is also found with regard to gender throughout the world: females have a significantly higher risk of having visual impairment than males. Notwithstanding the progress in surgical intervention that has been made in many countries over the last few decades, cataract remains the leading cause of visual impairment in all regions of the world, except in the most developed countries. Other major causes of visual impairment are, in order of importance, glaucoma, age-related macular degeneration, diabetic retinopathy and trachoma.
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            Adult-onset primary open-angle glaucoma caused by mutations in optineurin.

            Primary open-angle glaucoma (POAG) affects 33 million individuals worldwide and is a leading cause of blindness. In a study of 54 families with autosomal dominantly inherited adult-onset POAG, we identified the causative gene on chromosome 10p14 and designated it OPTN (for "optineurin"). Sequence alterations in OPTN were found in 16.7% of families with hereditary POAG, including individuals with normal intraocular pressure. The OPTN gene codes for a conserved 66-kilodalton protein of unknown function that has been implicated in the tumor necrosis factor-alpha signaling pathway and that interacts with diverse proteins including Huntingtin, Ras-associated protein RAB8, and transcription factor IIIA. Optineurin is expressed in trabecular meshwork, nonpigmented ciliary epithelium, retina, and brain, and we speculate that it plays a neuroprotective role.
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              Cerebrospinal fluid pressure in glaucoma: a prospective study.

              To assess whether a low cerebrospinal fluid pressure (CSF-P) is associated with open-angle glaucoma in eyes with normal intraocular pressure (IOP). Prospective, interventional study. The study included 43 patients with open-angle glaucoma (14 with a normal IOP, and 29 with an elevated IOP) and 71 subjects without glaucoma. All patients underwent standardized ophthalmologic and neurologic examinations and measurement of lumbar CSF-P. Cerebrospinal fluid pressure and IOP. Lumbar CSF-P was significantly (P<0.001) lower in the normal IOP glaucoma group (9.5+/-2.2 mmHg) than in the high IOP glaucoma group (11.7+/-2.7 mmHg) or the control group (12.9+/-1.9 mmHg). The trans-lamina cribrosa pressure difference (IOP minus CSF-P) was significantly (P<0.001) higher in the normal IOP glaucoma group (6.6+/-3.6 mmHg) and the high-IOP glaucoma group (12.5+/-4.1 mmHg) than in the control group (1.4+/-1.7 mmHg). The extent of glaucomatous visual field loss was negatively correlated with the height of the CSF-P and positively correlated with the trans-lamina cribrosa pressure difference. In the control group, CSF-P was significantly correlated with both systolic blood pressure (P = 0.04) and IOP (P<0.001). The trans-lamina cribrosa pressure difference was not significantly associated with blood pressure (P = 0.97). In open-angle glaucoma with normal IOP, CSF-P is abnormally low, leading to an abnormally high trans-lamina cribrosa pressure difference. Pathogenetically, a low CSF-P in normal-IOP glaucoma may be similar to a high IOP in high-IOP glaucoma. Consequently, the glaucomatous visual field defect is positively correlated with the trans-lamina cribrosa pressure difference and inversely correlated with the CSF-P. In nonglaucomatous subjects, CSF-P, blood pressure, and IOP are significantly associated with each other. Copyright (c) 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Br J Ophthalmol
                Br J Ophthalmol
                bjophthalmol
                bjo
                The British Journal of Ophthalmology
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0007-1161
                1468-2079
                February 2019
                26 October 2018
                : 103
                : 2
                : 161-166
                Affiliations
                [1] departmentVisual Research Project , Tokyo Metropolitan Institute of Medical Science , Tokyo 156-8506, Japan
                Author notes
                [Correspondence to ] Professor Takayuki Harada, Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; harada-tk@ 123456igakuken.or.jp
                Author information
                http://orcid.org/0000-0001-6167-0997
                Article
                bjophthalmol-2018-312724
                10.1136/bjophthalmol-2018-312724
                6362806
                30366949
                d693e2b8-81f9-44ae-97f4-631a1ea80e03
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0

                History
                : 12 June 2018
                : 21 August 2018
                : 25 August 2018
                Funding
                Funded by: Mitsui Life Social Welfare Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: JP15H04999JP16K07076JP16K08635JP16K11308JP17K07123JP18K19625
                Categories
                Review
                1506
                Custom metadata
                unlocked

                Ophthalmology & Optometry
                glaucoma,degeneration,drugs,experimental – animal models,experimental – laboratory

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