Early-Onset Glaucoma

Early-Onset Glaucoma

A novel high-throughput screening process has enabled scientists for the first time to identify molecules with the potential to block the accumulation of a toxic eye protein that can lead to early-onset glaucoma.

Researchers at the Georgia Institute of Technology in Atlanta, Georgia, identified the aggregated structure of a mutant protein called myocilin which may underlie the root cause of the protein’s contribution to increased intraocular pressure (IOP). Previous studies have shown that mutant myocilin is toxic to pressure-regulating cells in the eye and can damage the trabecular meshwork and impede fluid egress, thereby leading to elevated IOP.

To find molecules that bind to mutant myocilin and block its aggregation, researchers designed a simple, high-throughput assay and then screened a library of compounds. They identified two molecules with potential for future drug development to treat early-onset glaucoma.

“These are really the first potential targeted drug leads for glaucoma,” said Raquel Lieberman, an associate professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology in Atlanta, whose lab led the research.

It has been known for over a decade that mutant forms of myocilin lead to early-onset glaucoma, at least in part due to aggregation of the mutant protein, Dr Lieberman said. “In general, cells are able to handle mutant proteins by quickly promoting their degradation; however, this degradation process does not seem to be efficient in the trabecular meshwork [TM] of the eye challenged with mutant myocilin. Instead, TM cells die, leading to meshwork dysfunction and a hastening of ocular hypertension that leads to glaucoma.”

Mutant myocilin

Dr Lieberman said that her team’s research provides an explanation for why TM cells might encounter a particular challenge with mutant myocilin.

“Our extensive biophysical characterisation demonstrates that the aggregated form of mutant myocilin consists of a particularly stable, non-native structure called amyloid, that is resistant to degradation. Amyloids are common to other ageing and neurodegenerative diseases, most notably Alzheimer's where they form neurotoxic plaques in the brain,” she said.

Dr Lieberman noted that direct evidence of amyloid has now been demonstrated in vitro and in cells.

“We have used these systems to identify two compounds that bind to myocilin and reduce aggregation. We are extending our assays to test larger compound libraries. As we move forward, we will test our compounds in available animal models of early-onset glaucoma,” she said.

While the focus of this particular study was early-onset glaucoma, Dr Lieberman believes that it may well have important implications for other forms of glaucoma or ocular pathologies.

Dr Lieberman’s study was published in the journal ACS Chemical Biology.

 

Raquel Lieberman: raquel.lieberman@chemistry.gatech.edu

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