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3. Developing novel neuroprotective treatments for glaucoma that will complement and extend currently available treatment approaches

Drs. Zack, Quigley, and Welsbie

The ultimate cause of visual dysfunction and blindness in glaucoma is the dysfunction and death of retinal ganglion cells (RGCs), nerve cells that carry information from the eye to the brain. In advanced glaucoma, the patient does not see because RGCs die, and information is not communicated from the eye to the brain. The higher the eye pressure, the more RGC death from glaucoma, and lowering pressure slows the damage, but not completely. Thus, a protective strategy for RGCs (neuroprotection) that directly promotes the health and survival of RGCs has the potential to improve vision preservation for glaucoma. Such a therapy would likely be used in conjunction with current IOP-lowering drugs.

Project 1: As a first step towards developing a safe and effective neuroprotective drug, the GCE has created several High Content Screening (HCS) assays that can directly assess the ability of various small molecules to promote RGC survival, pointing to areas in which drugs could be developed. These assays use RGCs in culture, an approach that allows mass screening while remaining biologically relevant.

We have screened over 7,000 compounds, identifying a number of candidate RGC neuroprotective compounds. Collaborating with a team of chemists from Hopkins and outside, we will customize these compounds to make them suited for safe and effective human use. In parallel, we are testing the currently available compounds in well-characterized rodent models of glaucoma and RGC injury. Initial studies in these models confirm one compound with neuroprotective activity in animals. Further animal studies that should be predictive of eventual applicability to humans are also underway. In addition, the drug discovery work is being complemented by a number of ongoing studies in our labs that are analyzing the molecular mechanisms by which RGCs die in glaucoma.

This rational and logical pathway for the development of neuroprotective drugs for glaucoma is uniquely being used at the GCE. Although we have been fortunate to have received “start-up” funds from the National Institutes of Health to initiate the drug development work, along with our success comes an increasing demand for financial support, since chemical optimalization and animal testing are expensive. We are negotiating with pharmaceutical firms to collaborate in this work. Increased philanthropic support will allow us to extend and accelerate our drug development efforts. We expect that this work will lead to more effective and safer options for the prevention of glaucoma visual damage. Collaboration with Dr Nick Marsh-Armstrong of the Kennedy—Krieger Institute and Shannath Merbs of the Wilmer Institute is important in our ganglion cell studies. Additional funding of $250,000 is being sought.

Project 2: We recently developed a new model of glaucoma in mice that duplicates its more important features. Using this model that causes elevated eye pressure through obstruction of outflow by microbeads, we are not positioned to test a variety of factors using genetically and biochemically altered mice, in a way that is not feasible in any other species.

One major area of this work is to test the hypothesis that alteration in the biomechanical behavior of the sclera and its rheology will be protective for glaucoma. These experiments involve collaboration with engineers at both the Homewood and Medical School. Dr. Vicky Nguyen of the Mechanical Engineering Department collaborates with the Quigley lab to measure the stress—strain behavior of the mouse eye. We have determined that older age and certain biochemical treatments lead to stiffer sclera response. We will next test whether having a stiffer response to induced eye pressure elevation is beneficial in glaucoma. If so, treatments of human eyes to make the sclera stiffer are already being tested in corneal disease and could be made practical for glaucoma.

A second area is to breed mice with the equivalent of axial myopia and to test whether these are more susceptible to glaucoma, as are humans with axial myopia. The collaboration of Dr. Hal Dietz of the Department of Pediatrics is key to this work, as he has a strain of myopic mice that mimic the Marfan syndrome. We also are testing 5 other strains of mice from a variety of labs worldwide. The bead-induced mouse glaucoma model will be used in these experiments.

A third area of collaboration is with the Justin Hanes group, with whom we are working to measure the penetration of nanoparticles through the sclera. Scleral rheology has never been quantified, and this is quite important both to changes that may be induced by glaucoma, as well as delivery of drugs to the eye through the sclera.

Funding to underpin these projects could involve costs of $200,000.

 

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