Prospects for Neuroprotective Therapies in Glaucoma: Drug Targets and Emerging Clinical Strategies

Management of glaucoma is now at an inflection point with a new generation of therapeutic candidates, whilst targeting intraocular pressure-independent strategies is challenged by the landmark Phase III failure of memantine regarding trial design and endpoint sensitivity. Preclinical research has identified promising targets including glutamate excitotoxicity, neurotrophic factor deprivation, and mitochondrial dysfunction, with nicotinamide emerging as a leading candidate due to its ability to robustly protect RGCs by supporting NAD levels and bioenergetics. Current clinical efforts are expanding into metabolic repurposing with agents (eg metformin and semaglutide), sustained-delivery systems with neurotrophic factors (eg ciliary neurotrophic factor implant), and functional enhancers (eg citicoline). To bridge the translational gap, the field is integrating new endpoints with higher sensitivity (eg advanced assessment of photopic negative response), AI-guided endpoint selection (eg graph attention neural network), novel biomarkers (eg detection of apoptotic retinal cells and neurofilament light chain in aqueous humor), and precision medicine frameworks (eg polygenic risk scores and multi-omics analysis) to develop the first clinically validated neuroprotective treatments for glaucoma.