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CBTS researchers receive National Eye Institute grant

Could a therapeutic target for glaucoma that was once considered “undruggable” be the key to a first-of-its-kind treatment?

That was the question posed among friends and colleagues Dr. David Siderovski and Dr. Abbot Clark during one of their regular breakfast meetings at the Torched Apron Grill on The University of North Texas Health Science Center at Fort Worth campus.

That friendly conversation launched a collaborative project that just earned new research funding from The National Eye Institute of the National Institutes of Health. And it could lead to a new treatment for glaucoma, the leading cause of irreversible vision loss and blindness that affects more than 80 million people worldwide.

The project will target the bone morphogenic protein signaling antagonist Gremlin-1, seen to be elevated in the eyes of patients suffering from glaucoma. GREM1 causes a protein buildup in the front of the eye that increases the pressure within, leading to progressive vision loss and blindness if unchecked.

Abe Clark
Dr. Abe Clark

“Since the main activity of GREM1 is to bind and inhibit protective BMP proteins in the eye, there are no classical drug-binding sites within GREM1 as there are within enzymes or receptors, which are the two main targets of most current medicines,” said Clark, regents professor of pharmacology and neuroscience in the College of Biomedical and Translational Sciences and the North Texas Eye Research Institute.

“Therefore, GREM1 was classically considered to be an ‘undruggable’ target.”

However, recent advances in structural biology and machine learning are allowing the team to use their complementary expertise to attack the problem.

“In this new AI era, the notion of an undruggable target is outdated. By combining in silico docking — a computational technique that predicts how a drug candidate and protein will bind together– with biological testing, we hope to pioneer a new approach to glaucoma and create an innovative treatment,” said Siderovski, professor of pharmacology and neuroscience at CBTS.

David Siderovski
Dr. David Siderovski

With artificial intelligence, Siderovski’s lab team can speed the process of screening billions of virtual compounds for those rare few predicted to inhibit this protein-protein interaction.

Once a compound is identified, Clark’s lab, with a long-standing focus on cell biology and mouse models of glaucoma, will test its ability to lower intraocular pressure, a major causative risk factor for glaucoma.

“Glaucoma is the leading cause of irreversible vision loss and blindness, affecting more than 80 million individuals worldwide. I look forward to working with David to discover a novel disease-modifying therapy to better treat patients with vision-threatening glaucoma.” Clark said.

Award number R21EY036503. The content of this release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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