A vitamin-based therapy aimed at improving retinal metabolism may offer a new neuroprotective strategy for patients with glaucoma, according to new research published in Cell Reports Medicine. The study, led by scientists at Sweden’s Karolinska Institutet, found that supplements of vitamins B6, B9, B12, and choline slowed or halted damage to the optic nerve in animal models of glaucoma, even without reducing intraocular pressure (IOP), which is the goal of current glaucoma treatments.
Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by the death of retinal ganglion cells (RGCs), often triggered by elevated IOP. Current treatments such as eye drops, laser therapy, or surgery have the singular purpose of lowering IOP. But these approaches do not stop disease progression for all patients. Some develop glaucoma despite normal IOP, and others continue to lose vision even with successful pressure reduction.
The Karolinska team began their study by exploring the role of homocysteine, a metabolite linked to one-carbon metabolism and associated with other neurodegenerative conditions. Elevated homocysteine had been previously observed in glaucoma, prompting investigation into its significance. Analyzing both human and animal model data showed, however, that elevated homocysteine is not a causative factor in glaucoma.
“Our conclusion is that homocysteine is a bystander in the disease process, not a player,” said co-lead author James Tribble, PhD, an assistant professor in the department of clinical neuroscience at Karolinska Institutet. “Altered homocysteine levels may reveal that the retina has lost its ability to use certain vitamins that are necessary to maintain healthy metabolism. That’s why we wanted to investigate whether supplements of these vitamins could protect the retina.”
Experiments in animal models confirmed that modest elevations of homocysteine had no measurable effect on RGC survival. “Our study demonstrates that elevated homocysteine worsens glaucoma outcome in animal models but that this effect is mild. In humans, elevation of serum homocysteine has no detectable effect on glaucoma-related outcomes or disease progression,” the researchers wrote.
Instead, the investigators’ data pointed to a deeper issue: dysfunction in one-carbon metabolism, which involves essential vitamins and supports DNA methylation, mitochondrial activity, and oxidative stress defense. In both rodent models and human glaucoma tissue, the researchers identified early and sustained dysregulation of genes responsible for importing and using vitamins B6, B9, B12, and choline, which are essential in one-carbon metabolism.
Based on their findings and on earlier work that showed using various combinations of B6, B9, B12, and choline improve cognitive function in Alzheimer’s disease and reduce the risk of age-related macular degeneration, the researchers sought to find whether a similar approach could help treat glaucoma. The team’s experiments in mouse models that had slowly progressing glaucoma showed that damage to the optic nerve was entirely halted. In rats with more aggressive disease, the progression was significantly slowed. These improvements occurred without any intervention to reduce IOP, suggesting there is an IOP-independent mechanism of action that contributes to glaucoma progression.
These findings build on earlier research by the same group and others, which showed metabolic dysfunction—including loss of mitochondrial function and energy capacity—preceded detectable RGC degeneration in glaucoma. In this study, the added insight was that one-carbon metabolism, a less-explored aspect of retinal health, is disrupted early in the disease and can be targeted with vitamin therapy.
Based on these promising preclinical results, the researchers have begun a clinical trial at St Eriks Eye Hospital in Stockholm. The trial includes patients with both primary open-angle glaucoma and pseudoexfoliation glaucoma to evaluate whether the vitamin combination can provide similar neuroprotective effects in humans.
While the doses used in animals were carefully translated to human-equivalent doses, researchers acknowledge some exceed current tolerable upper intake levels, particularly for choline and folate. “Testing of B6, B9, B12, and choline in a clinical trial setting for glaucoma will be necessary to fully determine their utility for preventing neurodegeneration and maintaining visual function in glaucoma patients,” the researchers wrote.
While these new findings show potential, the research had its limitations. The researchers have yet to definitively prove that the protective effect of vitamin supplementation results directly from the correction of one-carbon metabolism dysfunction. In addition, the human data were mostly derived from patients with primary open-angle glaucoma, and further research is needed to determine if the same mechanisms apply across other glaucoma subtypes.
