Genetic susceptibility and neuroprotective gene therapy of normal tension glaucoma: a review

Normal-tension glaucoma (NTG) is a distinct form of glaucomatous optic neuropathy characterized by progressive retinal ganglion cell (RGC) degeneration and visual field loss despite intraocular pressure (IOP) remaining within the statistically normal range. Although IOP reduction remains the only established disease-modifying strategy, continued disease progression despite adequate IOP control highlights the importance of IOP-independent mechanisms. Increasing evidence implicates vascular dysregulation, mitochondrial dysfunction, oxidative stress, impaired autophagy, neuroinflammation, axonal transport abnormalities, and circadian dysregulation in increased RGC vulnerability. Genetic studies have identified OPTN and TBK1 as the most strongly supported NTG-associated susceptibility genes, whereas many other candidate genes, including MYOC, SARM1, DLK, BDNF, NOS3, KLF2 and PTGDS, are shared with other glaucoma subtypes or remain supported primarily by experimental or mechanistic evidence. These interconnected processes converge on mitochondrial impairment, axonal degeneration, and RGC death, providing potential therapeutic targets beyond conventional IOP lowering. This review integrates the vascular, mitochondrial, and neuronal mechanisms underlying NTG, distinguishes NTG-associated molecular factors from pathways shared across glaucoma subtypes, and summarizes emerging gene- and nucleic-acid-based therapeutic strategies. By linking evidence-based mechanisms with emerging molecular technologies, this review provides a framework for mechanism-based and precision-oriented therapies that may complement established IOP-lowering treatment for NTG.