Discovery of novel disease modifying therapy for the prevention and treatment of glaucoma - R21 Grant Proposal Discovery of disease modifying therapy for the prevention and treatment of glaucoma Abbot F. Clark, PhD and David P. Siderovski, PhD Pharmacology & Neuroscience UNTHSC Abstract: Glaucoma is the leading cause of irreversible vision loss and blindness in the world affecting 80 million individuals worldwide. Current glaucoma treatments are directed at lowering intraocular pressure (IOP), the main risk factor for the development and progression of glaucoma. While these pharmaceutical or surgical therapies may slow vision loss, the majority of glaucoma patients continue to lose vision. Also, IOP lowering treatments do not directly address the underlying glaucomatous damage to the eye, making patients increasingly resistant to therapy over time. There is a definite need to discover better ways to treat glaucoma, including new disease modifying therapies that directly intervene and prevent glaucomatous damage to the eye. Our research has focused on discovering the molecular mechanisms responsible for this glaucomatous damage, and we recently discovered intersecting pathogenic signaling pathways (TGFβ2/BMP/GREM1) that damage the front of the eye causing IOP elevation and the back of the eye causing optic nerve degeneration. Based on this pathogenic mechanism discovery, we will employ new computational pharmacological approaches to identify novel agents that will interfere with the GREM1-BMP protein-protein interaction (PPI), using 3D molecular dynamics modeling of GREM1-BMP2/4 structures to allow for in silico screening of an extensive library of small molecules for potential PPI inhibitors (Specific Aim #1a). We then will screen these candidate inhibitors using surface plasmon resonance (SPR) binding assays (Specific Aim #1b), trabecular meshwork cell culture assays (Specific Aim 2), and in vivo mouse ocular hypertension assays (Specific Aim #3) to identify, refine, and validate these drug candidates as new glaucoma disease modifying therapies. This cutting-edge research will lead to the first of its kind therapy to directly intervene in the glaucomatous disease process leading to glaucoma pathology.
