Neuroprotection in Glaucoma
Glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell degeneration and visual field loss, is a leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is currently the only modifiable risk factor for this disease. However, glaucomatous damage persists in almost 50% of patients, despite lowering IOP. Neuroprotection in glaucoma refers to non-IOP-related interventions that can prevent or delay glaucomatous neurodegeneration, independently of IOP. The current article reviews and discusses the various strategies for neuroprotection in glaucoma to date.
Brimonidine is an alpha-2 adrenergic agonist commonly used as an anti-glaucoma, IOP-lowering agent. Previous studies using animal models have shown enhanced survival of retinal ganglion cells (RGCs) independently of IOP. Brimonidine also protects RGCs from somatic, axonal, and dendritic degeneration in optic injuries involving ischemia, NMDA-induced neurotoxicity, ocular hypertension, optic crush, and optic neuritis.In its ophthalmic formulation, brimonidine must reach effective pharmacologic concentrations in the vitreous to have an effect on the retina. In a clinical study of phakic, aphakic, and pseudo-phakic patients undergoing pars plana vitrectomy, topical brimonidine 0.2% administered twice daily for 5 to 14 days prior to surgery yielded 2 nM in the vitreous, satisfying the threshold concentration for neuroprotection . Various mechanisms for brimonidine’s neuroprotective effects have been purported including neurotrophic factor activation, vasomodulation, glutamate inhibition, and cell-survival signal upregulation as well as apoptosis downregulation. Specifically, brimonidine increases the transcription of neurotrophic factors (e.g. brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF)) and their receptors (TrkB for BDNF and FGF receptor), which regulate various cellular functions including neuronal growth, plasticity, differentiation, and survival. Brimonidine has been shown to not only protect the retina from ischemic damage in a dose- and time-dependent manner, but also to support neural regeneration after injury. Brimonidine also mitigates neuronal death and promotes cell survival by decreasing Bax (pro-apoptotic) while increasing Bcl-2/xL (anti-apoptotic) expressions in injured cells, respectively. Brimonidine further provides anti-cytotoxic benefits by decreasing post-injury glutamate accumulation.
Mohamed et al. conducted a single-center, nonrandomized study evaluating brimonidine’s effects on visual field performance in 16 primary open-angle glaucoma (POAG) patients with medically controlled IOP. Visual fields were assessed at baseline, 6 months, and 12 months after administering 0.2% brimonidine twice daily. IOP significantly decreased at 6 and at 12 months. With respect to field field parameters, mean deviation significantly increased at 6 and at 12 months, whereas pattern standard deviation did not significantly improve for either time points. Overall, brimonidine improved visual field performance and also lowered IOP. Whether these neuroprotective effects were independent of IOP is not clear.
The Low-pressure Glaucoma Treatment Study (LoGTS) compared the effects of brimonidine and timolol on visual field progression in low-pressure glaucoma. In this multicenter, double-masked, randomized study, 99 patients were treated with brimonidine and 79 patients were treated with timolol. The incidence of visual field progression was significantly lower for patients receiving brimonidine monotherapy relative to the timolol group (9.1% and 39.2%, respectively), despite similar IOP-lowering effects. Notably, however, 55% of patients in the brimonidine cohort and about 30% of patients in the timolol cohort were lost to follow-up over the course of the study. Approximately half of those lost to follow up in the brimonidine group experienced ocular allergy, which may have potentially skewed the study’s findings. Additional clinical studies conducted by Tsai et al. reported a statistically significant reduction in retinal nerve fiber layer (RNFL) damage following the use of brimonidine 0.2% compared with timolol 0.5% in ocular hypertensive patients over 1 year, independently of IOP reduction.
Stem Cell Therapy
Mesenchymal Stromal Cells
Mesenchymal stromal cells (MSCs) have also been implicated in glaucoma neuroprotection. Studies using animal models and postmortem human tissues suggest an MSC association with neuroprotective factors, namely platelet-derived growth factor (PDGF). However, this neuroprotective approach is not without shortcomings as intravitreal injection of MSCs may similarly have adverse effects including reactive gliosis, vitreous clumping, and epiretinal membrane thickening.  These unfavorable changes may be related to variability in cell preparation methodologies and standardized protocols are likely necessary to further elucidate the neuroprotective role of MSCs. The secretome of MSCs, including MSC derived neurotrophins and exosomes that can be used as carriers for various cell signaling molecules are currently being investigated as therapeutic agents. 
Human Embryonic Stem Cells
Human embryonic stem cells (hESCs) are pluripotent cells with the capacity to differentiate into all 3 embryonic layers. Experimental studies conducted by Sluch et al. have developed cell culture protocols for differentiating hESCs into RGCs. Previous preclinical studies (in mature uninjured rat and monkey eyes) have also demonstrated successful integration of hESCs and their mediation of light responses in the host retina. However, given the embryonic nature of hESCs, this technology is both an ethically controversial and scientifically challenging approach to neuroprotection in ocular disease.
Clinical trials currently investigating the role of stem cells in glaucoma include the following:
- The Intravitreal Mesenchymal Stem Cell Transplantation in Advanced Glaucoma Study: Phase I study evaluating the safety of intravitreally injecting autologous MSCs in 10 patients (NCT02330978). 
- Stem Cell Ophthalmology Treatment Study and Stem Cell Ophthalmology Treatment Study II: Non-randomized, open-label, patient-funded studies assessing variability in patient outcomes according to different methods of MSC delivery including sub-Tenon’s, retrobulbar, intravitreal or intravenous route (NCT01920867, NCT03011541).
- The Effectiveness and Safety of Adipose-Derived Regenerative Cells for Treatment of Glaucomatous Neurodegeneration study: Single-arm, uncontrolled study evaluating the efficacy of stem cells delivered via the sub-Tenon’s route (NCT02144103).
Overall, the clinical utility of cell-based therapies is poorly understood. Despite the potential neuroprotective or neuroregenerative roles of stem cells, randomized and controlled clinical trials are necessary to sufficiently demonstrate the practical applications of stem cell therapy in glaucoma. There are few clinical trials using stem cells and their derivatives in glaucoma, and most have not reported any results, although the animal studies have been promising. A viable and promising alternative is the use of exosomes and miRNAs that would reduce the risks of unpredictable stem cell transplants. 
Exosomes contain a variety of biological active substances such as proteins, miRNAs, and lipids. They are involved in many pathological processes such as nerve injury and repair, vascular regeneration and immune response. Exosomes extracellular vesicles between 30-150nm in diameter and are widely found in all biological fluids, including blood, milk, urine, saliva, sweat and tears. They have been implicated in playing an important role in glaucoma and other eye diseases  Mead and Tomarev, in an optic nerve crush model, found that BMSC exosomes significantly promoted survival and axonal regeneration of RGCs through a miRNA dependent mechanism.  A separate class of extracellular vesicles termed, Matrix-Bound Nanovesicles, have also showed potential in pre-clinical studies to promote RGC survival and regeneration after injury through modulation of the immune system.  However, further preclinical and clinical studies are needed to elucidate the therapeutic potential of exosomes and other vesicles diseases. 
Ciliary Neurotrophic Factor
The hypothalamic neuropeptide, ciliary neurotrophic factor (CNTF), is a neuronal survival factor that may potentially confer neuroprotection in glaucoma. Currently, Neurotech Pharmaceuticals is conducting a randomized, sham-controlled, masked Phase II clinical trial using NT-501, an implantable polymeric device, to deliver encapsulated CNTF in 54 glaucoma patients. Following intravitreal implantation, the semi-permeable membrane encasement enables sustained CNTF release by retinal pigment epithelial cells targeting the retinal ganglion cells (NCT02862938). In Phase I of this trial, 11 participants with POAG were implanted with high-dose CNTF-secreting NT-501 implant and followed for 18 months with the contralateral eye serving as the control. Visual acuity, contrast sensitivity, mean HVF visual field index and RNFL thickness all decreased more in the control eyes than in the implanted eyes. Phase II clinical trial is underway. 
Recombinant Human Nerve Growth Factor
Recombinant human nerve growth factor (rhNGF) is an effective neuroprotective agent with a favorable safety and efficacy profile. Notably, ophthalmic formulations of rhNGF are FDA-approved for treating neurotrophic keratitis. Clinical trials investigating the role of rhNGF in glaucoma are currently underway. The NGF-Glaucoma trial is a Phase 1b, monocentric, double-masked randomized study, which aims to assess the safety and tolerability of rhNGF ophthalmic solution compared to a vehicle control in chronic POAG patients. Structural and functional evaluations using optical coherence tomography, visual field, and electroretinography (ERG) are secondary objectives (NCT02855450). Phase 1b of this study through 32 weeks showed no treatment-related adverse effects, however also showed no statistically significant differences in global indices of visual fields or RNFL thickness between the groups, although both structure and function measures showed non-significant trends toward significance in favor of rhNGF. 
Brain‑derived Neurotrophic Factor
Oddone et al. reported decreased brain‑derived neurotrophic factor (BDNF) and NGF levels in early glaucoma, and therefore proposed these growth factors as biomarkers for detecting early disease. Additional evidence has shown that administering trophic factors in combination (neurturin, GDNF, and BDNF) more effectively enhances RGC survival relative to administering these factors alone.
Gene therapy strategies for glaucoma neuroprotection are rising of interested, although currently limited in clinical applications. Experimental studies conducted by Jain et al. in juvenile open angle glaucoma effectively lowered IOP and inhibited glaucomatous damage by inducing loss-of-function mutations in the myocilin gene in mouse models of myocilin-associated POAG. Human cell-cultures similarly exhibited decreased trabecular meshwork myocilin mRNA following myocilin gene mutations. Various investigators are also studying tunica interna endothelial cell kinase (TEK) as a genetic target. Given its role as an angiopoietin receptor involved in Schlemm’s canal development, disruption of this gene is associated with various phenotypes of congenital glaucoma. Therefore, inducing gain-of-function mutations in TEK may have potential value in gene therapy.
Additional strategies include genetically delivering neuroprotective factors to mitigate retinal ganglion cell loss. In particular, genetic constructs designed by Astellas Pharmaceuticals enable the overexpression of BDNF and TrkB. This dual delivery of both the neuroprotective ligand and its receptor allows for the prolonged activation of ganglion cell survival pathways and may prove to be a reliable therapeutic approach to POAG in the planned Phase I/IIa trials. For a more complete list of preclinical and clinical studies investigating gene therapy for glaucoma and other ocular conditions, visit the review written by He et al. 
Ocular Blood Flow Regulating Agents
Aside from IOP, vascular dysregulation has also been suggested in glaucoma pathogenesis. Notably, anti-glaucoma medications including carbonic anhydrase inhibitors, such as dorzolamide, and prostaglandin analogs, such as latanoprost, have been shown to improve ocular perfusion in addition to lowering IOP. Experimental studies in animal models of retinal ischemia have also demonstrated the neuroprotective effects of betaxolol, a selective beta-2 adrenergic antagonist. However, the precise mechanisms of neuroprotection conferred by these agents or whether these effects occur independently of IOP are unclear and further investigations are necessary.
Ginkgo biloba extract (GBE) has various antioxidant effects and has been suggested as a neuroprotective agent in neurodegenerative diseases including cognitive impairment and Alzheimer’s Disease (AD). Mitochondrial dysfunction and oxidative stress have both been purported in dementia and glaucoma pathogenesis. Not surprisingly, given this mechanistic overlap, researchers have similarly explored the potential therapeutic benefits of GBE in glaucoma. A crossover randomized clinical trial comprising 27 normal tension glaucoma (NTG) patients evaluated the effects of GBE on visual field performance in patients receiving 40 mg GBE three times daily for 4 weeks followed by 4 weeks of placebo (separated by an 8-week washout period) compared to patients receiving the placebo treatment first followed by GBE. NTG patients receiving GBE showed significant improvements in visual field indices. In a 4-year longitudinal study conducted by Lee et al., NTG patients treated with GBE also showed marked improvement in visual field performance and without significant IOP changes. Alternatively, a crossover, placebo‑controlled, clinical trial showed no improvement in visual field performance or contrast sensitivity in Chinese NTG cohorts treated with GBE. In addition to its anti-oxidant effects, GBE also has vascular regulatory effects and has been shown to improve ocular blood flow. Color Doppler studies have demonstrated increased blood flow velocity and decreased vascular resistance in the retrobulbar as well as peripapillary vascular networks of NTG patients. A clinical trial is currently underway to further establish the effects of GBE on ocular blood flow in POAG (NCT02376114), however there have been no published findings since the study completion date, February 2014.
Memantine is a non-competitive NMDA antagonist with anti-glutamate excitotoxicity effects. Though typically indicated in moderate to severe AD, memantine has also been shown to protect against RGC loss in animal models of glaucoma. Despite these potentially promising neuroprotective findings, large-scale multicenter, randomized double-masked placebo-controlled Phase III clinical trials failed to demonstrate significant benefits with memantine therapy in patients with glaucoma (NCT00141882, NCT00168350).
Citicoline (cytidine 5’-diphosphocholine) is an endogenous compound and an emerging therapeutic agent for glaucoma. Clinical studies have recently investigated the neuroprotective effects of citicoline in glaucoma in its intramuscular (IM), oral, and topical eye drop formulations. Giraldi et al. first described the neurotrophic properties of citicoline for treating POAG in 1989, whereby patients treated with IM citicoline 1 g daily for 10 days all showed significant improvement in visual field testing, despite well-controlled IOP. These therapeutic effects continued for at least 3 months and were maintained with retreatment. Giraldi and investigators also evaluated citicoline’s protective effects with repeated cycles of therapy every 6 months and found that the perimetric benefits persisted for over 10 years. Visual field worsening fractions in treated patients and controls were 10% and 50%, respectively. Placebo-controlled studies have also demonstrated significant improvements in retinocortical function with IM citicoline as measured by visual evoked potentials (VEP) and pattern ERG (PERG)
Rejdak et al. was the first to evaluate the neuroprotective effects of oral citicoline in glaucoma. VEP significantly normalized in amplitude and implicit time in glaucomatous eyes treated with 2, bi-weekly courses of 500 mg tablets containing citicoline. Studies have similarly reported improved VEP amplitude and retinocortical time in chronic POAG patients treated with oral citicoline. Longitudinal investigations have further evaluated the benefits of oral citicoline in patients with progressing POAG, despite controlled IOP. Patients treated with oral citicoline 500 mg daily (4-month cycles separated by 2-month wash-out periods) over 2 years showed a significant reduction in glaucomatous progression rate, averaging -0.15 +/- 0.3 dB/year. Additional studies have reported delayed glaucomatous damage in retinal morphology, whereby OCT thickness measurements of the RNFL and the ganglion cells complex markedly improved with oral citicoline therapy. Intriguingly, however, the significance of these results was not apparent until after 1-year of citicoline therapy, suggesting that extended treatment is needed to achieve clinically meaningful effects. Parisi et al. compared the efficacies of oral and IM citicoline and reported similar improvements in retinal function and neural conduction along visual pathways for both formulations. Continued therapy for up to 8 years stabilized or further improved visual dysfunction in glaucoma patients, suggesting the need for repeated dosing to achieve optimal results.
Topical administration of citicoline eye drops has also been shown to improve retinal function and neural conduction along the visual pathway, as measured by PERG and VEP. Although these effects are similar to that of oral citicoline, enhanced penetration for reaching therapeutic levels of topical citicoline in the vitreous is associated with increasingly probable adverse effects. In contrast, oral citicoline has very minimal or absent side effects as well as improved compliance and is the preferred route of administration. In fact, citicoline is authorized as a food supplement in the European Union (EU), Italian Ministry of Health, and the United States. Citicoline is approved in the EU and Italian Ministry of Health, as a novel food ingredient in food supplements and in dietary foods for special medical purposes in glaucoma patients.
Calcium Channel Blockers
Calcium channel blockers (CCBs) have been implicated in glaucoma neuroprotection by preventing calcium-mediated apoptosis and improving ocular blood flow. In particular, brovincamine and nilvadipine are 2 CCB’s that permeate the blood-brain barrier and, thus, selectively influence the optic nerve circulation without appreciably affecting systemic circulation. Randomized clinical trials have demonstrated the therapeutic effects of brovincamine and nilvadipine, whereby NTG patients treated with CCBs showed improved ocular blood flow and delayed progression of visual field defects. Despite their selectivity, however, these CCBs may impair ocular blood flow autoregulation, especially during acute increases in IOP. In addition, non-selective CCBs should be prescribed with caution since reduced systemic blood pressure can compromise blood flow to the optic nerve and potentially contribute to glaucoma pathogenesis.
Decreased antioxidant levels in conjunction with increased oxidative free radical damage have been implicated in glaucoma pathogenesis. In fact, studies have demonstrated trabecular meshwork (TM) degeneration followed by IOP elevation and subsequent glaucomatous damage in human tissues. Additional studies have reported significant correlations between oxidative damage in TM gene expression and increased IOP as well as visual field loss. Among the various antioxidants, Coenzyme Q10 (CoQ10), a cofactor of the mitochondrial respiratory chain, may be useful in scavenging free radicals and minimizing oxidative stress. A 12-month clinical trial evaluated the efficacy of Coqun (CoQ10 plus vitamin E) ophthalmic solution along with beta-blockers in glaucoma patients compared to patients treated with beta-blockers alone. Glaucoma patients receiving the combined regimen featured improved inner retinal function and visual cortical responses, as determined by PERG and VEP, respectively.
Nicotinamide (vitamin B3 or NAM), an important precursor for nicotinamide adenine dinucleotide (NAD), has a favorable neuroprotective profile in glaucoma given its integral roles in calcium homeostasis, endothelin-mediated vascular regulation, and maintenance of mitochondrial function. NAM neuroprotection in glaucoma has largely been demonstrated in animal models and independently of IOP. However, Nzoughet et al. recently reported significantly reduced plasma NAM levels in POAG patients relative to controls, which further support NAM’s neuroprotective properties. In addition, the safety and efficacy of oral NAM have already been demonstrated in a Phase III randomized clinical trial (UTN U1111-1131-4069). In light of these reassuring preliminary findings, the Center for Eye Research in Australia is currently conducting the first clinical trial to assess the short-term therapeutic effects of NAM supplementation in POAG patients (Trial ID ACTRN12617000809336).
Netarsudil, a Rho-Kinase inhibitor, is already being used for the management of high intraocular pressure. ROCK are serine/threonine kinases that play an important role in fundamental processes of cell migration, proliferation and survival.  Blockade of ROCK promotes axonal regeneration and neuroprotection. Elevated levels of rho enzymes have been found in the optic nerve head of glaucomatous eyes as compared with age-matched controls, supporting a possible role for rho in glaucomatous neuropathy. Both fasudil and netarsurdil have been reported to arrest axonal degeneration, promote axonal regeneration , and have been found to increase ocular blood flow.  While neuroprotective activity of ROCK inhibitors has been demonstrated in the eye, further studies are warranted. 
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