Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

Abstract

Purpose: The eye is currently at the forefront of translational medicine and therapeutics. However, despite advances in technology, primary open-angle glaucoma remains the leading cause of irreversible blindness worldwide. Traditional intraocular pressure (IOP)-lowering therapies are often not sufficient to prevent progression to blindness, even in patients with access to high-quality healthcare. Neuroprotection strategies, which aim to boost the ability of target cells to withstand a pathological insult, have shown significant promise in animal models but none have shown clinically relevant efficacy in human clinical trials to date. We sought to evaluate the current status of neuroprotection clinical trials for glaucoma and identify limitations which have prevented translation of new glaucoma therapies to date. Methods: Literature searches identified English language references. Sources included MEDLINE, EMBASE, the Cochrane Library and Web of Science databases; reference lists of retrieved studies; and internet pages of relevant organisations, meetings and conference proceedings, and clinical trial registries. Results: We discuss six key neuroprotective strategies for glaucoma that have reached the clinical trial stage. Delivery of neurotrophic factors through gene therapy is also progressing towards glaucoma clinical trials. Refinements in trial design and the use of new modalities to define structural and functional endpoints may improve our assessment of disease activity and treatment efficacy. Advances in our understanding of compartmentalised glaucomatous degeneration and continued progress in the molecular profiling of glaucoma patients will enable us to predict individual risk and tailor treatment. Conclusion: New approaches to future glaucoma neuroprotection trials could improve the prospects for new glaucoma therapies. Glaucoma treatment tailored according to an individual's unique risk profile may become increasingly common in the future. ARTICLE HISTORY

Innovative IOP-Independent Neuroprotection and Neuroregeneration Strategies in the Pipeline for Glaucoma

“…In addition, regeneration of nonviable RGCs and their axons would be highly desirable to restore and maintain functional vision. However, randomized clinical trials investigating oral memantine and topical brimonidine have not demonstrated a clear neuroprotection benefit in patients with glaucoma [11,15]. For the latter pharmacologic agent, patients with low-pressure glaucoma had slightly less visual field progression with topical administration of the alpha2-adrenergic agonist brimonidine tartrate 0.2% compared to the beta-adrenergic antagonist timolol maleate 0.5% [15].…”

“…Currently accepted strategies for treatment of POAG, whether medical, laser, or incisional surgical modalities, aim to lower IOP below a presumed threshold level [ 4 , 8 , 9 ]. Though these IOP-lowering therapies have been proven to slow and/or halt progression of the glaucomatous damage and therefore are neuroprotective in nature, slow progress has been made in developing IOP-independent neuroprotection and/or neuroregeneration strategies [ 10 , 11 ]. While neuroprotection strategies to enhance the ability of target cells in the central nervous system (CNS) to withstand pathological insults have shown substantive promise in animal models, none have been reported to be clinically effective in human clinical trials [ 11 ].…”

“…Though these IOP-lowering therapies have been proven to slow and/or halt progression of the glaucomatous damage and therefore are neuroprotective in nature, slow progress has been made in developing IOP-independent neuroprotection and/or neuroregeneration strategies [ 10 , 11 ]. While neuroprotection strategies to enhance the ability of target cells in the central nervous system (CNS) to withstand pathological insults have shown substantive promise in animal models, none have been reported to be clinically effective in human clinical trials [ 11 ]. In addition, early stage intervention to prevent disease development and/or progression would likely require evolution of improved algorithms and technologies to enable and/or enhance this earlier detection.…”

The Effect of Dietary Vitamin K1 Supplementation on Trabecular Meshwork and Retina in a Chronic Ocular Hypertensive Rat Model

“…3 Hence, innovative approaches of neuroprotection are necessary to develop more potential options for glaucoma treatment. 4 Oxidative stress is presumed to play a crucial role in the neurodegenerative process of glaucoma. 5 Apart from its neurodegenerative effect on the optic nerve, oxidative stress has also been shown to damage another major target tissue of glaucoma: trabecular meshwork (TM).…”

“… 3 Hence, innovative approaches of neuroprotection are necessary to develop more potential options for glaucoma treatment. 4 …”