New Study Uncovers Potential Glaucoma Therapeutic Target

Researchers have identified a metabolically sensitive cell subtype in the eye's drainage system which shows early signs of dysfunction in a genetic mouse model of glaucoma. The study, published in eLife, provides what the editors say are fundamental findings, highlighting a potential therapeutic strategy for preventing or slowing the development of glaucoma. Glaucoma, a group of eye diseases that damage the optic nerve, is a leading cause of irreversible blindness that affects 80 million people worldwide as of 2020. One of the main risk factors is high intraocular pressure, which often results from dysfunction in the trabecular meshwork—a porous tissue that helps maintain normal eye pressure by allowing fluid to drain from the eye. The trabecular meshwork is located in the limbal region, which forms the border between the cornea (the clear outer layer of the eye) and the sclera (the white of the eye). "Despite its importance, little is known about the cellular diversity within the trabecular meshwork, or how individual subtypes of these cells are susceptible to dysfunction," says co-lead author Nicholas Tolman, a Postdoctoral Research Scientist in the Department of Ophthalmology, Columbia University Vagelos College of Physicians and Surgeons, New York, US. "We set out to create a detailed molecular map of the trabecular meshwork and to identify the cells most affected in glaucoma." Tolman served as co-lead author of the study alongside Taibo Li, an MD Ph.D. intern / resident physician at Johns Hopkins University, Baltimore, US, and Revathi Balasubramanian, Assistant Professor of Ophthalmology, Columbia University Vagelos College of Physicians and Surgeons. Mapping cell types in the eye Tolman and colleagues used single-cell RNA sequencing, a method that reveals which genes are active in individual cells, to profile nearly 18,000 cells from the limbal region of two strains of healthy mice. They identified six major cell types, with further analysis revealing three subtypes of trabecular meshwork cells, which they named TM1, TM2 and TM3. The identities of these subtypes were confirmed across multiple datasets, laboratories, and through immunofluorescence—which uses glowing tags to visualize specific proteins—and in situ hybridization, which shows where particular genes are active in a tissue. Each TM subtype showed distinct molecular signatures and spatial organization. TM1 cells were enriched for genes that are crucial for extracellular matrix production, suggesting a role in maintaining tissue structure. TM2 cells expressed genes linked to cell signaling and phagocytosis—a process where a cell engulfs and internalizes foreign particles—hinting at a role in immune response and debris clearance. TM3 cells stood out for their high levels of mitochondrial and contractility-related genes, as well as elevated expression of Lmx1b, a gene previously linked to glaucoma in both mice and humans. Investigating glaucoma-associated stress To investigate how these subtypes respond to glaucoma-associated stress, the team used a mouse model carrying a dominant mutation in Lmx1b, mimicking genetic glaucoma. While all three TM subtypes were present in these mice, TM3 cells were most affected. They showed signs of mitochondrial dysfunction, reduced oxidative phosphorylation (a key energy-producing pathway), and often lowered expression of genes involved in protein quality control. These disruptions likely impair the function and health of TM3 cells, affecting their ability to properly regulate outflow and pointing to TM3 as a critical cell type in glaucoma progression. "While our work shows a clear effect of the Lmx1b mutation on mitochondria, future studies will be needed to see if and how Lmx1b directly modulates mitochondrial genes in mutant TM cells," Tolman says. Testing potential therapeutic strategies Finally, the team tested whether supporting mitochondrial function could help protect the eye from glaucoma progression. They treated some of the mice with nicotinamide, a form of vitamin B3 known to enhance cellular metabolism and improve resilience. This led to lower eye pressure and fewer signs of the anatomical changes linked to glaucoma progression, compared to the mice that did not receive treatment. These results suggest that supporting TM3 cells metabolically could offer a new avenue to prevent or slow glaucoma development, although more studies are needed to validate the findings and provide a fuller mechanistic understanding of vitamin B3's therapeutic effects. "Our study provides a comprehensive characterization of mouse trabecular meshwork cells, offering much-needed information on the cell subtypes that are dysregulated in glaucoma," says senior author Simon John, a Professor in the Department of Ophthalmology, Columbia University Vagelos College of Physicians and Surgeons, and the Zuckerman Mind Brain Behavior Institute, Columbia University. "This information could lead to new therapies that target the cells most vulnerable to damage, potentially preventing or delaying vision loss. It will be interesting to determine whether similar cell types exist in the human eye and whether interventions like nicotinamide could offer lasting protection in clinical settings."