What started as a breakfast meeting question has led to the awarding of new research funding from The National Eye Institute of the National Institutes of Health to researchers at the University of North Texas Health Science Center at Fort Worth.
What was the question friends and colleagues Drs. David Siderovski and Abbot Clark discussed during one of their regular breakfast meetings at the Torched Apron Grill on the UNTHSC campus?
Could a therapeutic target for glaucoma that was once considered “undruggable” be the key to a first-of-its-kind treatment?
UNTHSC said the pair’s friendly conversation launched a collaborative project that just earned the new research funding. 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, UNTHSC said.
The school said the project will target the bone morphogenic protein signaling antagonist Gremlin-1 that is seen to be elevated in the eyes of patients suffering from glaucoma. GREM1 causes a protein buildup in the front of the eye, UNTHSC said, that increases the pressure within, leading to progressive vision loss and blindness if unchecked.
“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,” Clark, regents professor of pharmacology and neuroscience in the College of Biomedical and Translational Sciences (CBTS) and the North Texas Eye Research Institute, said in a statement. “Therefore, GREM1 was classically considered to be an ‘undruggable’ target.”
Game-changing role of AI
Recent advances in structural biology and machine learning, however, are allowing the team to use their complementary expertise to attack the problem, UNTHSC said.
“In this new AI era, the notion of an undruggable target is outdated.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,” Siderovski, professor of pharmacology and neuroscience at CBTS, said.
With artificial intelligence, UNTHSC said that 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.
It said that once a compound is identified, Clark’s lab, which has 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.
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