Glaucoma is considered to be a heterogeneous group of conditions giving retinal ganglion cells (RGC) damage. Lowering intraocular pressure (IOP) reduces the risk of progressive RGC loss in glaucoma. Regeneration of the optic nerve has been shown to restore some visual function in animal models. The authors discuss future treatment strategies with a combined neuroprotective / neuroregenerative approach. Pharmacological neuroprotection: Compounds targeting modulation of glutamate-induced excitotoxicity, inhibition of nitric oxide synthase or the endothelin pathway, oxidative stress, and inhibition of glial activity have been shown to be neuroprotective in animal models of glaucoma. Laboratory studies have demonstrated that systemic administration of brimonidine provides RGC neuroprotection in animal glaucoma models independent of its effect on IOP.
This neuroprotective effect is thought to be mediated via a variety of mechanisms including brain derived neurotrophic factor (BDNF) and basic fibroblast growth factor upregulation, the activation of cell survival signalling pathways and prevention of apoptosis and α2 modulation of N-methyl-D-aspartate (NMDA) receptor function. In human clinical trials, brimonidine monotherapy lowered the incidence of visual field progression compared to timolol treated patients (9 vs. 30%) in the Low-Pressure Glaucoma Study Group, over a period of 30 months in patients who were able to tolerate the treatment. In addition, brimonidine administered topically twice a day for two weeks prior to vitrectomy achieved 2nM in the vitreous which was at a sufficient concentration for neuroprotection in previous animal studies.
Memantine is a non-competitive NMDA receptor antagonist used in the treatment of Alzheimer’s disease and showed promising results in a monkey model of glaucoma. However, in large scale Phase III clinical trials there was no evidence of any statistical benefit compared to placebo in reducing visual field progression. Mesenchymal stem cells: Mesenchymal stem cells (MSCs) have been shown to be neuroprotective in Parkinson’s disease, multiple sclerosis and spinal cord injury. They are easy to obtain from adult bone marrow. This avoids ethical concerns and the need for immune suppression. MSCs have been shown to be neuroprotective in a rat glaucoma model. An analysis of the protective factors produced by MSCs strongly implicated platelet-derived growth factor (PDGF) and subsequent blockage of PDGF signalling prevents MSC-mediated neuroprotection in animal models. However, PDGF and MSCs can induce reactive gliosis in retinal Muller cells and astrocytes with upregulation of intermediate filament proteins and retinal folding. Proinflammatory vitreous clumping of MSCs injected intravitreally as well as thick epiretinal membrane formation following MSC administration in humans have been reported. Gene therapy: Retinal gene replacement strategies designed to augment loss of function have been used with encouraging safety and efficacy in Leber’s congenital amaurosis and choroideraemia.
Advances are being made in RGC disease and clinical trials are currently underway to evaluate the efficacy of GS010, an adeno-associated virus type 2 (AAV2) construct containing the NADH dehydrogenase subunit 4 (ND4) gene to treat patients with Leber’s Hereditary Optic Neuropathy due to the G11778A ND4 mitochondrial mutation. Additional gene-based strategies include the delivery of genes encoding therapeutic proteins such as neurotrophic factors. AAV2 mediated delivery of BDNF and ciliary neurotrophic factor (CNTF) have been shown to confer RGC neuroprotection in experimental glaucoma. – SR
