The 2024–2025 Pipeline for IOP-Independent Neuroprotection in Glaucoma

This audio article is from VisualFieldTest.com.Read the full article here: https://visualfieldtest.com/en/the-2024-2025-pipeline-for-iop-independent-neuroprotection-in-glaucomaTest your visual field online: https://visualfieldtest.comExcerpt:Introduction Glaucoma is a common eye disease that damages retinal ganglion cells (RGCs) – the nerve cells that carry visual signals from the eye to the brain – leading to irreversible vision loss. Most treatments focus on lowering eye pressure (intraocular pressure or IOP), which indeed slows damage in many patients (). However, a large fraction of glaucoma patients lose vision even when their IOP is normal or well-controlled. This has sparked great interest in IOP-independent neuroprotection – therapies aimed directly at keeping RGCs alive by targeting other stressors. Long-term RGC damage in glaucoma has been linked not only to pressure, but also to poor blood flow, excess excitation by brain chemicals (excitotoxicity), and oxidative stress (damaging molecules in cells) (). New treatments in development are striving to protect RGCs through several strategies: stabilizing cell mitochondria (the RGC “power plants”), supplying neurotrophic factors (growth signals), dialing down inflammation, and calming overactive immune cells (microglia). Below we review key late-stage candidates in these categories, explain their mechanisms and trial progress, and discuss how modern trial designs and biomarkers may finally yield success after past disappointments.Mitochondrial Stabilizers RGCs have very high energy needs. Mitochondria within RGCs produce ATP (energy) but can also generate harmful free radicals. Drugs or nutrients that stabilize mitochondria and boost healthy metabolism are a major focus. For example, nicotinamide (vitamin B3) is a precursor for NAD^+, a co-factor that fuels energy production. In glaucoma models, high-dose nicotinamide greatly protected RGCs () (). This led to a large human trial: starting in 2022 the UK‐led study aims to enroll ~500 patients for 4 years to test whether nicotinamide delays vision loss (). This trial will also measure mitochondrial “power” in blood cells and other biomarkers (). Early small trials of high-dose nicotinamide already hinted that some patients improved vision (). Despite its promise, nicotinamide can cause flushing or nausea at very high doses, so trial safety is being watched closely. Citicoline (CDP-choline) is another mitochondrial enhancer. It helps build cell membranes and supports energy metabolism. Clinical studies (mostly outside the US) report that citicoline supplements (oral drops or pills) can slow glaucoma progression or improve visual function (). Indeed, long-term studies have shown treated patients had less field loss and better quality-of-life, independent of IOP (). Citicoline is well tolerated, and eye-drop forms are already registered for glaucoma in Europe. (In contrast to past failures, experts expect official approvals in more countries ahead ().) Other mitochondrial approaches are in early/preclinical stages. For example, the NDI1 gene therapy (AAV-NDI1) directly boosts mitochondrial respiration. In glaucoma mice, a single monthly eye injection of AAV-NDI1 protected RGCs and improved their electrical responses (). This approach uses a virus to deliver a powerful yeast-derived enzyme that works in RGC mitochondria. The company behind it (Vzarii Therapeutics) plans to move toward human trials, but this is likely several years away. Meanwhile, common supplements like coenzyme Q10 (CoQ10) or pyruvate are also believed to scavenge free radicals and support mitochondria. Early studies suggest they may help RGC function, but definitive clinical trials are still pendinSupport the show