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Cutting-Edge Research Finds Targets for New Glaucoma Treatments

Glaucoma increases intraocular pressure (IOP) in the eyes, eventually damaging the optic nerve and often leading to irreversible blindness. Eyedrop and pill medications can reduce IOP by limiting eye water production or increasing its outflow, but the root causes for most glaucomas are unknown, and there are no cures.

Pseudoexfoliation (PEX) glaucoma is notable for the fluffy white deposits clinicians observe on lens surfaces. While this dandruff-like material gives PEX glaucoma a distinctive diagnostic feature, nobody knows what actually drives the disease.

To better understand PEX glaucoma’s underlying causes, researchers at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine recently used cutting-edge metabolomic studies to identify molecules that contribute to PEX pathology. Their work was published in the journal Molecular Omics.

“By determining the metabolic changes occurring in the eye during this vision-threatening disease process, we may be better able to understand how these proteins are affecting the eye, causing damage and leading to permanent and irreversible blindness,” said Sanjoy Bhattacharya, Ph.D., professor of ophthalmology and senior author on the paper. “From there, we can study the molecular targets in this type of glaucoma and hopefully develop treatments.”

To learn more about PEX glaucoma’s biology, the team used highly sensitive mass spectrometry to examine eye water for PEX metabolites — small molecules produced when larger ones are broken down (metabolized). Because these molecules can be biologically active, identifying them is an important step toward understanding how the disease occurs and researching new, targeted drug therapies.

Mass spectrometry produces massive datasets that are complex to manage and interpret. The Bascom Palmer team applied artificial intelligence to condense the data and help them understand the results — a new approach to metabolomic discovery.

The researchers performed these studies on three groups: individuals with normal eyes, patients with primary open angle glaucoma (the most common form of the disease) and patients with PEX glaucoma.

While there were many commonalities, the scientists found significantly different metabolite signatures in each type of glaucoma, including 125 metabolites unique to PEX glaucoma. Of these, 11 warranted further study.

“If we know which particular metabolites are deleterious and dysregulated, we can potentially target and customize molecular therapy to treat or even cure this eye disease to protect and save vision,” said Richard K. Lee, M.D., Ph.D., associate professor of ophthalmology and the Walter G. Ross Chair of Ophthalmology, a co-author on the study. “For example, if there are high concentrations of a specific oxidative molecule, we can treat it with a targeted reducing agent to counteract those effects.”

In addition to providing potential therapeutic targets, these results could be used to improve glaucoma diagnostics. Having a precise molecular readout could help subdivide patients based on their unique disease profiles, advance individualized therapies and lead to earlier disease detection. Glaucoma is irreversible, so early detection is critical to preserving sight.

“Because we have a molecular signature for these patients with advanced disease, we may be able to use that information to detect the disease much earlier, even before the pseudoexfoliation protein is visible,” said Anna Junk, M.D., professor of clinical ophthalmology and another co-author on the study.

While PEX is commonly associated with glaucoma, this condition can be found in several organs and may be linked to other conditions. The researchers believe these insights will support continuing efforts to understand and possibly treat all its variations.

“This material is all over the body,” Dr. Bhattacharya said. “It’s in the heart, the lungs — everywhere. And though the links haven’t been proven yet, PEX may increase the risk of heart attack, stroke, abdominal aortic aneurisms and other systemic diseases.”

Tags: Anna Junk, Bascom Palmer, PEX glaucoma, Richard K. Lee, Sanjoy Bhattacharya