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

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.

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma

“…These results suggested that aRGCs and ipRGCs have high tolerance to IOP-independent pathogenic factors that may be involved in the progress of glaucoma. 32 We showed that aRGCs and ipRGCs are tolerant to glutamate neurotoxicity. Our findings are supported by a recent study demonstrating that susceptibility of different types of genetically identified RGCs to NMDA excitotoxicity varies significantly, and that aRGCs are the most resistant RGCs to NMDA excitotoxicity.…”

“…[29][30][31] Retinal degeneration in GLAST knockout (KO) mice may occur due to various factors, such as aging, glutamate neurotoxicity, and oxidative stress, which are important risk factors in human glaucoma. 32 Previous studies have reported that glaucoma patients show downregulation of glutamate transporters and glutathione levels, 33,34 suggesting that GLAST KO mice are useful as animal models of NTG.…”

“…38,39 Glutamate excitotoxicity is thought to have important roles in RGC death in many retinal diseases, such as glaucoma, diabetic retinopathy, optic nerve injury, and retinal ischemia. 32,[39][40][41][42] Therefore, these experimentally-induced RGC death models are useful for exploring neuroprotective strategies that could lead to glaucoma therapy. 43,44 We examined aRGCs and ipRGCs to determine if there are any subtype-specific or region-specific responses to NMDA treatment or to NTG-like neurodegeneration in GLAST KO mice.…”

Changes of Ocular Dimensions as a Marker of Disease Progression in a Murine Model of Pigmentary Glaucoma

“…Animal models provide valuable information about the diagnosis and course of disease. They also enable the development of new therapeutic approaches and allow for the monitoring of effects of the therapy (Harada et al, 2019). The DBA/2J mice strain is commonly used as an animal model that mimics many aspects of congenital human glaucoma, particularly pigmentary glaucoma (PG).…”

Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead

“…Several issues contributing to the lack of success of drugs in clinical trials could be suggested, but in the case of glaucoma, the lack of an animal model that fully mimics the human disease is an important factor that adds to this failure [331]. Another issue is that, in preclinical trials, several studies use a preventive strategy to assess the effect of a specific drug, as opposed to the human condition in which the treatment starts after diagnosis.…”