Neuroprotection in glaucoma: current and emerging approaches

Abstract

Neuroprotection in glaucoma aims to prevent degeneration of RGCs, independent of reduction in intraocular pressure, in order to maintain visual function. The vast potential for neuroprotection to prevent decline in visual function and preserve quality of life has stimulated research into multiple therapeutic approaches. Current strategies have focused on drug therapies that have the ability to preserve visual function by prevention of RGC apoptosis. There is promise in new treatments in stem cell and gene therapy. Despite such innovation, there has been a delay in translating research from bench to the clinic; conventional clinical trial designs in glaucoma have proven to be lengthy, expensive and difficult to define. This review highlights new and emerging approaches in neuroprotection for glaucoma. Additionally, it explores the ability of alternative clinical trial design to investigate therapeutic concepts and facilitate the development of novel therapy for patients.

Keywords::

• adaptive design
• axon regeneration
• clinical trials
• excitotoxicity
• futility design
• gene therapy
• mitochondrial dysfunction
• neuroprotection
• neurotrophic factors
• optic nerve
• RGC
• stem cell

Financial & competing interests disclosure

MF Cordeiro is an inventor on patent applications owned by UCL and pertaining to Detection of Apoptosing Retinal Cells. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Neuroprotection is the concept of limitation of retinal ganglion cell (RGC) degeneration and preservation of visual function.

• Current treatment approaches have focused on inhibition of RGC apoptosis. These include treatment approaches targeting excitotoxicity, mitochondrial dysfunction, oxidative stress, inflammation and adrenergic activation.

• Memantine is an N-methyl-D-aspartate antagonist targeting excitotoxicity-induced apoptosis. It failed to show treatment response compared with placebo in a clinical trial, although details about the trial itself remain unpublished.

• Neurotrophic factors have been implicated in the preservation of neuronal cells. Short half-life, limited permeability and low intracellular concentration in target cells limit neurotrophic capacity. Sustained delivery of neurotrophic factors through stem cell transplantation may improve treatment efficacy.

• Inhibition of pro-apoptotic proteins (such as BCL2 and BCLxL) through adenoviral-associated vectors-mediated gene knockdown has prevented apoptosis of RGCs in rodent models of glaucoma.

• Translation of neuroprotection to clinical trials is difficult due to the natural history of glaucoma, variability of clinical response and inadequacy of current end point determination.

• Intraocular pressure is not suitable as an end point in trials of neuroprotection. New end points in glaucoma are being developed such as detection of apoptosis retinal cells, and the combination of existing methods involving structural and functional measures is being explored.

• Alternative clinical trial designs include futility design, adaptive (Bayesian) design and long-term simple study trial designs.

Notes