Degeneration Of Retinal Ganglion Cells Research Articles

The genetic basis for adult onset glaucoma: Recent advances and future directions.

Glaucoma, a diverse group of eye disorders that results in the degeneration of retinal ganglion cells, is the world's leading cause of irreversible blindness. Apart from age and ancestry, the major risk factor for glaucoma is increased intraocular pressure (IOP). In primary open-angle glaucoma (POAG), the anterior chamber angle is open but there is resistance to aqueous outflow. In primary angle-closure glaucoma (PACG), crowding of the anterior chamber angle due to anatomical alterations impede aqueous drainage through the angle. In exfoliation syndrome and exfoliation glaucoma, deposition of white flaky material throughout the anterior chamber directly interfere with aqueous outflow. Observational studies have established that there is a strong hereditable component for glaucoma onset and progression. Indeed, a succession of genome wide association studies (GWAS) that were centered upon single nucleotide polymorphisms (SNP) have yielded more than a hundred genetic markers associated with glaucoma risk. However, a shortcoming of GWAS studies is the difficulty in identifying the actual effector genes responsible for disease pathogenesis. Building on the foundation laid by GWAS studies, research groups have recently begun to perform whole exome-sequencing to evaluate the contribution of protein-changing, coding sequence genetic variants to glaucoma risk. The adoption of this technology in both large population-based studies as well as family studies are revealing the presence of novel, protein-changing genetic variants that could enrich our understanding of the pathogenesis of glaucoma. This review will cover recent advances in the genetics of primary open-angle glaucoma, primary angle-closure glaucoma and exfoliation glaucoma, which collectively make up the vast majority of all glaucoma cases in the world today. We will discuss how recent advances in research methodology have uncovered new risk genes, and how follow up biological investigations could be undertaken in order to define how the risk encoded by a genetic sequence variant comes into play in patients. We will also hypothesise how data arising from characterising these genetic variants could be utilized to predict glaucoma risk and the manner in which new therapeutic strategies might be informed.

Analysis of retinal vasculature changes in indirect traumatic optic neuropathy using optic coherence tomography angiography.

To assess the retinal vasculature alterations in indirect traumatic optic neuropathy (ITON) patients following craniofacial trauma by optic coherence tomography angiography (OCTA). Patients diagnosed of monocular ITON were recruited from August 2016 to May 2020. OCTA was performed using the AngioVue OCT-A system for two cube scans centered at the optic nerve head and fovea. OCTA data included thicknesses of peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC), as well as proportion of capillary perfusion and data were analyzed for correlation with post-injury timepoints: within 7, 8-30, 31-90, and 91-365d. A total of 73 ITON patients were studied. Significant thinning of RNFL and GCC layers and attenuation of microvascular perfusion were observed in ITON eyes as compared to contralateral unaffected eyes (for most of the analyzed sectors and quadrants, P<0.05). Without respect to surgical intervention and vision recovery, the decrease in retinal layer thicknesses and microvascular perfusion was time-dependent, and most significant within three months (P<0.001). ITON presents with time-dependent thinning of retinal layers and attenuation of microvasculature, indicating possible degeneration of retinal ganglion cells due to reduced retinal blood supply.

Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

Subtype-specific survival and regeneration of retinal ganglion cells in response to injury.

Retinal ganglion cells (RGCs) are a heterogeneous population of neurons that function synchronously to convey visual information through the optic nerve to retinorecipient target areas in the brain. Injury or disease to the optic nerve results in RGC degeneration and loss of visual function, as few RGCs survive, and even fewer can be provoked to regenerate their axons. Despite causative insults being broadly shared, regeneration studies demonstrate that RGC types exhibit differential resilience to injury and undergo selective survival and regeneration of their axons. While most early studies have identified these RGC types based their morphological and physiological characteristics, recent advances in transgenic and gene sequencing technologies have further enabled type identification based on unique molecular features. In this review, we provide an overview of the well characterized RGC types and identify those shown to preferentially survive and regenerate in various regeneration models. Furthermore, we discuss cellular characteristics of both the resilient and susceptible RGC types including the combinatorial expression of different molecular markers that identify these specific populations. Lastly, we discuss potential molecular mechanisms and genes found to be selectively expressed by specific types that may contribute to their reparative capacity. Together, we describe the studies that lay the important groundwork for identifying factors that promote neural regeneration and help advance the development of targeted therapy for the treatment of RGC degeneration as well as neurodegenerative diseases in general.

Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that results from degeneration of retinal ganglion cells (RGC). Mitochondrial ND4 11778G > A mutation, which affects structural components of complex I, is the most prevalent LHON-associated mitochondrial DNA (mtDNA) mutation worldwide. The m.11778G > A mutation is the primary contributor underlying the development of LHON and X-linked PRICKLE3 allele (c.157C > T, p.Arg53Trp) linked to biogenesis of ATPase interacts with m.11778G > A mutation to cause LHON. However, the lack of appropriate cell and animal models of LHON has been significant obstacles for deep elucidation of disease pathophysiology, specifically the tissue-specific effects. Using RGC-like cells differentiated from induced pluripotent stem cells (iPSCs) from members of one Chinese family (asymptomatic subjects carrying only m.11778G > A mutation or PRICKLE3 p.Arg53Trp mutation, symptomatic individuals bearing both m.11778G > A and PRICKLE3 p.Arg53Trp mutations and control lacking these mutations), we demonstrated the deleterious effects of mitochondrial dysfunctions on the morphology and functions of RGCs. Notably, iPSCs bearing only m.11778G > A or p.Arg53Trp mutation exhibited mild defects in differentiation to RGC-like cells. The RGC-like cells carrying only m.11778G > A or p.Arg53Trp mutation displayed mild defects in RGC morphology, including the area of soma and numbers of neurites, electrophysiological properties, ATP contents and apoptosis. Strikingly, those RGC-like cells derived from symptomatic individuals harboring both m.11778G > A and p.Arg53Trp mutations displayed greater defects in the development, morphology and functions than those in cells bearing single mutation. These findings provide new insights into pathophysiology of LHON arising from RGC deficiencies caused by synergy between m.11778G > A and PRICKLE3 p.Arg53Trp mutation.

A Small Natural Molecule S3 Protects Retinal Ganglion Cells and Promotes Parkin-Mediated Mitophagy against Excitotoxicity.

Glutamate excitotoxicity may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other optic neuropathies, leading to irreversible blindness. Growing evidence has linked impaired mitochondrial quality control with RGCs degeneration, while parkin, an E3 ubiquitin ligase, has proved to be protective and promotes mitophagy in RGCs against excitotoxicity. The purpose of this study was to explore whether a small molecule S3 could modulate parkin-mediated mitophagy and has therapeutic potential for RGCs. The results showed that as an inhibitor of deubiquitinase USP30, S3 protected cultured RGCs and improved mitochondrial health against NMDA-induced excitotoxicity. Administration of S3 promoted the parkin expression and its downstream mitophagy-related proteins in RGCs. An upregulated ubiquitination level of Mfn2 and protein level of OPA1 were also observed in S3-treated RGCs, while parkin knockdown resulted in a major loss of the protective effect of S3 on RGCs under excitotoxicity. These findings demonstrated that S3 promoted RGC survival mainly through enhancing parkin-mediated mitophagy against excitotoxicity. The neuroprotective value of S3 in glaucoma and other optic neuropathies deserves further investigation.

Changes in retinal nerve fibre layer, ganglion cell layer and visual function in eyes with thyroid eye disease of different severities with and without orbital decompression.

To evaluate progressive changes in retinal nerve fibre layer (RNFL), ganglion cell layer/inner plexiform layer (GCL/IPL) and visual function in thyroid eye disease (TED) patients with and without orbital decompression. Sixty TED patients (105 eyes) were included. All patients were divided into mild, moderate-to-severe and dysthyroid optic neuropathy (DON) groups. Orbital decompression was performed in the moderate-to-severe and DON groups. Optic coherence tomography (OCT), visual field (VF) and best-corrected visual acuity (BCVA) were performed pre- and postoperatively. Preoperative follow-up was performed in the mild group and in part of the moderate-to-severe and DON groups. After decompression, the thickness of GCL/IPL and RNFL significantly decreased in DON group (p < 0.05), with varying degrees of decrease in eyes with optic disc swelling, atrophy and normal appearance. The mean GCL/IPL thickness significantly decreased in moderate-to-severe group (p < 0.05), the mean RNFL thickness slightly decreased with no statistical significance (p = 0.07). During the preoperative follow-ups, the mean GCL/IPL thickness significantly decreased (p = 0.04), whereas the mean RNFL thickness tended to increase (p = 0.13) in DON group. The thickness of GCL/IPL and RNFL did not change significantly in the mild and moderate-to-severe groups (p > 0.05). BCVA and VF did not change significantly in any group (p > 0.05) preoperatively. Swelling and degeneration of retinal ganglion cells (RGCs) may coexist in DON eyes, leading to continuous changes in the RNFL and GCL/IPL thickness either before or after decompression. Slight swelling and degeneration of RGCs may exist in moderate-to-severe TED eyes, although OCT measurements and visual functions remain stable before surgery.

Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function

Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line, Sema6ACreERT2, that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line, Opn4CreERT2, to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.

Generation of an induced pluripotent stem cell line from a patient with leber's hereditary optic neuropathy carrying a homoplasmic m.3635G > A mutation in the mitochondrial ND1 gene

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease that usually leads to selective degeneration of retinal ganglion cells (RGCs) and optic atrophy in young adults. One of three common mitochondrial DNA (mtDNA) mutations (m.11778G > A, m.3460G > A, m.14484 T > C) account for 90% of LHON cases. All three affect the function of respiration chain complex I. However, m.3635G > A, affecting the structure and function of MT-ND1 gene, is also associated with LHON. Here, we successfully generated a human induced pluripotent stem cell (hiPSC) line from an LHON patient carrying a homoplasmic m.3635G > A mutation in the MT-ND1 gene.

Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.

SummaryLeber’s hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.

ID:16464 Electrical Optic Nerve Stimulation Improves Visual Fields in Elderly Glaucoma Patients

Glaucoma is characterized by optic nerve degeneration and loss of retinal ganglion cells causing visual field impairment (1). The current standard approach in glaucoma therapy is reduction of the intraocular pressure (IOP). Despite effective medications leading to IOP-lowering, glaucoma exacerbation and progressive vision loss among patients is common. Visual field loss in patients over 65 years of age progresses with a worsening rate of 0.74 dB/year (2). Electrical stimulation of the optic nerve (ONS) facilitates axonal regeneration and survival of retinal ganglion cells (3). The follow-up study provides real-world evidence for long-term clinical efficacy of ONS in glaucoma.

Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells.

SummaryAlthough the degeneration of retinal ganglion cells (RGCs) is a primary characteristic of glaucoma, astrocytes also contribute to their neurodegeneration in disease states. Although studies often explore cell-autonomous aspects of RGC neurodegeneration, a more comprehensive model of glaucoma should take into consideration interactions between astrocytes and RGCs. To explore this concept, RGCs and astrocytes were differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated OPTN(E50K) mutation along with corresponding isogenic controls. Initial results indicated significant changes in OPTN(E50K) astrocytes, including evidence of autophagy dysfunction. Subsequently, co-culture experiments demonstrated that OPTN(E50K) astrocytes led to neurodegenerative properties in otherwise healthy RGCs, while healthy astrocytes rescued some neurodegenerative features in OPTN(E50K) RGCs. These results are the first to identify disease phenotypes in OPTN(E50K) astrocytes, including how their modulation of RGCs is affected. Moreover, these results support the concept that astrocytes could offer a promising target for therapeutic intervention in glaucoma.

Direct induction of human retinal ganglion cell-like cells using human transcription factors

<p indent="0mm">Direct reprogramming of somatic cell transdifferentiates somatic cells from one cell type into another, providing a new strategy to explore the pathological mechanisms and therapeutic methods for neural degeneration diseases. Glaucoma is the most prevalent retinal degenerative disease caused by the degeneration and death of retinal ganglion cells (RGC) and their axons. Our previous study showed that <italic>Ascl1</italic>,<italic> Brn3b</italic>,<italic> </italic>and <italic>Islet1</italic> transcription factor combination can efficiently reprogram mouse fibroblasts into functional RGC-like cells (induced RGCs, iRGCs). Here, we investigated whether this transcription factor combination can also achieve efficient human iRGC (hiRGC) induction. For this purpose, we used lentiviruses to introduce mouse <italic>Ascl1</italic>, <italic>Brn3b</italic>, and<italic> Islet1</italic>, or human <italic>ASCL1</italic>, <italic>BRN3B</italic>, and <italic>ISLET1</italic> cDNAs into human fibroblasts, and used the Tet-ON strategy to control the expression of the exogenous genes. At specific time points after induction, we performed immunofluorescent staining to examine the expression of the representative neuron or RGC marker genes and patch clamp to evaluate the electrophysiological membrane properties of the induced cells. The results showed that by replacing mouse <italic>Ascl1</italic>, <italic>Brn3b</italic>, and <italic>Islet1</italic> cDNAs with human <italic>ASCL1</italic>, <italic>BRN3B</italic>, and<italic> ISLET1</italic> cDNAs, human fibroblasts could also be reprogrammed into hiRGCs. Furthermore, by adding the human <italic>SOX4 </italic>gene, highly efficient hiRGCs induction was achieved. The obtained iRGCs showed mature neuronal morphology, expressed various neuron-specific proteins, and exhibited the electrophysiological characteristics of functional neurons. Our study provided a valuable cell source for studying the RGC cell fate determination mechanism and exploring translational applications for retinal diseases, such as glaucoma.

Selective Upregulation of SIRT1 Expression in Retinal Ganglion Cells by AAV-Mediated Gene Delivery Increases Neuronal Cell Survival and Alleviates Axon Demyelination Associated with Optic Neuritis.

Optic neuritis (ON), the most common ocular manifestation of multiple sclerosis, is an autoimmune inflammatory demyelinating disease also characterized by degeneration of retinal ganglion cells (RGCs) and their axons, which commonly leads to visual impairment despite attempted treatments. Although ON disease etiology is not known, changes in the redox system and exacerbated optic nerve inflammation play a major role in the pathogenesis of the disease. Silent information regulator 1 (sirtuin-1/SIRT1) is a ubiquitously expressed NAD+-dependent deacetylase, which functions to reduce/prevent both oxidative stress and inflammation in various tissues. Non-specific upregulation of SIRT1 by pharmacologic and genetic approaches attenuates RGC loss in experimental ON. Herein, we hypothesized that targeted expression of SIRT1 selectively in RGCs using an adeno-associated virus (AAV) vector as a delivery vehicle is an effective approach to reducing neurodegeneration and preserving vision in ON. We tested this hypothesis through intravitreal injection of AAV7m8.SNCG.SIRT1, an AAV2-derived vector optimized for highly efficient SIRT1 transgene transfer and protein expression into RGCs in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis that recapitulates optic neuritis RGC loss and axon demyelination. Our data show that EAE mice injected with a control vehicle exhibit progressive alteration of visual function reflected by decreasing optokinetic response (OKR) scores, whereas comparatively, AAV7m8.SNCG.SIRT1-injected EAE mice maintain higher OKR scores, suggesting that SIRT1 reduces the visual deficit imparted by EAE. Consistent with this, RGC survival determined by immunolabeling is increased and axon demyelination is decreased in the AAV7m8.SNCG.SIRT1 RGC-injected group of EAE mice compared to the mouse EAE counterpart injected with a vehicle or with control vector AAV7m8.SNCG.eGFP. However, immune cell infiltration of the optic nerve is not significantly different among all EAE groups of mice injected with either vehicle or AAV7m8.SNCG.SIRT1. We conclude that despite minimally affecting the inflammatory response in the optic nerve, AAV7m8-mediated SIRT1 transfer into RGCs has a neuroprotective potential against RGC loss, axon demyelination and vison deficits associated with EAE. Together, these data suggest that SIRT1 exerts direct effects on RGC survival and function.

Regulatory mechanisms of retinal ganglion cell death in normal tension glaucoma and potential therapies.

Normal tension glaucoma (NTG) is a multifactorial optic neuropathy characterized by normal intraocular pressure, progressive retinal ganglion cell (RGC) death, and glaucomatous visual field loss. Recent studies have described the mechanisms underlying the pathogenesis of NTG. In addition to controlling intraocular pressure, neuroprotection and reduction of RGC degeneration may be beneficial therapies for NTG. In this review, we summarized the main regulatory mechanisms of RGC death in NTG, including autophagy, glutamate neurotoxicity, oxidative stress, neuroinflammation, immunity, and vasoconstriction. Autophagy can be induced by retinal hypoxia and axonal damage. In this process, ischemia can cause mutations of optineurin and activate the nuclear factor-kappa B pathway. Glutamate neurotoxicity is induced by the over-stimulation of N-methyl-D-aspartate membrane receptors by glutamate, which occurs in RGCs and induces progressive glaucomatous optic neuropathy. Oxidative stress also participates in NTG-related glaucomatous optic neuropathy. It impairs the mitochondrial and DNA function of RGCs through the apoptosis signal-regulating kinase-JUN N-terminal kinase pathway. Moreover, it increases inflammation and the immune response of RGCs. Endothelin 1 causes endothelial dysfunction and impairment of ocular blood flow, promoting vasospasm and glaucomatous optic neuropathy, as a result of NTG. In conclusion, we discussed research progress on potential options for the protection of RGCs, including TANK binding kinase 1 inhibitors regulating autophagy, N-methyl-D-aspartate receptor antagonists inhibiting glutamate toxicity, ASK1 inhibitors regulating mitochondrial function, and antioxidants inhibiting oxidative stress. In NTG, RGC death is regulated by a network of mechanisms, while various potential targets protect RGCs. Collectively, these findings provide insight into the pathogenesis of NTG and potential therapeutic strategies.

Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells.

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterized by the preferential loss of retinal ganglion cells (RGCs), resulting in optic nerve degeneration and progressive bilateral central vision loss. More than 60% of genetically confirmed patients with DOA carry variants in the nuclear OPA1 gene, which encodes for a ubiquitously expressed, mitochondrial GTPase protein. OPA1 has diverse functions within the mitochondrial network, facilitating inner membrane fusion and cristae modelling, regulating mitochondrial DNA maintenance and coordinating mitochondrial bioenergetics. There are currently no licensed disease-modifying therapies for DOA and the disease mechanisms driving RGC degeneration are poorly understood. Here, we describe the generation of isogenic, heterozygous OPA1 null induced pluripotent stem cell (iPSC) (OPA1+/−) through clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing of a control cell line, in conjunction with the generation of DOA patient-derived iPSC carrying OPA1 variants, namely, the c.2708_2711delTTAG variant (DOA iPSC), and previously reported missense variant iPSC line (c.1334G>A, DOA plus [DOA]+ iPSC) and CRISPR/Cas9 corrected controls. A two-dimensional (2D) differentiation protocol was used to study the effect of OPA1 variants on iPSC-RGC differentiation and mitochondrial function. OPA1+/−, DOA and DOA+ iPSC showed no differentiation deficit compared to control iPSC lines, exhibiting comparable expression of all relevant markers at each stage of differentiation. OPA1+/− and OPA1 variant iPSC-RGCs exhibited impaired mitochondrial homeostasis, with reduced bioenergetic output and compromised mitochondrial DNA maintenance. These data highlight mitochondrial deficits associated with OPA1 dysfunction in human iPSC-RGCs, and establish a platform to study disease mechanisms that contribute to RGC loss in DOA, as well as potential therapeutic interventions.

From Bench to Bedside-Delivering Gene Therapy for Leber Hereditary Optic Neuropathy.

Leber hereditary optic neuropathy (LHON) is a rare, maternally inherited mitochondrial disorder that presents with severe bilateral sequential vision loss, due to the selective degeneration of retinal ganglion cells (RGCs). Since the mitochondrial genetic basis for LHON was uncovered in 1988, considerable progress has been made in understanding the pathogenetic mechanisms driving RGC loss, which has enabled the development of therapeutic approaches aimed at mitigating the underlying mitochondrial dysfunction. In this review, we explore the genetics of LHON, from bench to bedside, focusing on the pathogenetic mechanisms and how these have informed the development of different gene therapy approaches, in particular the technique of allotopic expression with adeno-associated viral vectors. Finally, we provide an overview of the recent gene therapy clinical trials and consider the unanswered questions, challenges, and future prospects.

Drainage glaucoma surgery

Glaucoma is a chronic disease characterized by optical neuropathy, progressive degeneration of retinal ganglion cells and nerve fiber layer, and is the leading cause of irreversible blindness in the world. Currently, the most reliable way to achieve stable normalization of intraocular pressure is surgical treatment, and its success is measured by the duration of the hypotensive effect. However, surgical interventions do not always have a prolonged effect. One of the most drastic and effective ways of treating patients with glaucoma is surgery involving installation of a drainage implant. The use of implants in the area of surgical intervention is the most effective way to preserve the outflow routes of intraocular fluid created during antiglaucoma interventions. The use of implants is aimed at reducing excessive scarring in the filtration zone and at creating ways of resorption of intraocular fluid. In the history of glaucoma surgery, numerous designs for drainage implants have been proposed, differing from each other in material, drainage structure, implantation technique, and results. This literature review describes the types of anti-glaucoma drainage devices and their latest modifications, and presents the statistics of postoperative complications and long-term results of the use of foreign- and Russian-made implants in the treatment of glaucoma.

Optic nerve crush as a model of retinal ganglion cell degeneration

Background: Axonal degeneration caused by damage to the optic nerve can result in a gradual death of retinal ganglion cells (RGC), leading to irreversible vision loss. An example of such diseases in humans includes optic nerve degeneration in glaucoma. Glaucoma is characterized by the progressive degeneration of the optic nerve and the loss of RGCs that can lead to loss of vision. The different animal models developed to mimic glaucomatous neurodegeneration, all result in RGC loss consequent optic nerve damage.

From Bench to Bed: The Current Genome Editing Therapies for Glaucoma.

Glaucoma is a group of optic neuropathies featured by degeneration of retinal ganglion cells and loss of their axons in the optic nerve. The only currently approved therapies focus on lowering intraocular pressure with medication and surgery. Over the previous few decades, technological advances and research progress regarding pathogenesis has brought glaucomatous gene therapy to the forefront. In this review, we discuss the three current genome editing methods and potential disease mechanisms of glaucoma. We further summarize different genome editing strategies that are being developed to target a number of glaucoma-related genes and pathways from four aspects including strategies to lower intraocular pressure, neuroprotection, RGC and optic nerve neuro-regeneration, and other strategies. In summary, genome therapy is a promising therapy for treating patients with glaucoma and has great potential to be widely applied in clinical practice.