Development of a New Medicine for Inherited Glaucoma

Wing (Chris) Lee, PhD
Mayo Clinic Jacksonville (Jacksonville, FL, United States)
Year Awarded:
Grant Duration:
July 1, 2012 to June 30, 2014
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southeastern

Development of a Novel Therapeutic for Inherited Glaucoma


The study proposes to develop a new type of medicine for a common form of glaucoma related to mutations in a gene called MYOC. Some inherited mutations can change the structure and property of myocilin protein, which can lead to toxicity and dysfunction of the eye cells responsible for regulating eye pressure. Dr. Wing Lee and colleagues will attempt to identify drug-like chemical compounds that can bind to and stabilize the structure of the mutated myocilin, which subsequently may delay the onset of the disease or slow down disease progression by correcting abnormal changes at molecular level.


Primary open-angle glaucoma (POAG) is the most common form of glaucoma. While the mechanisms that cause POAG are not completely understood, patients with POAG normally have increased eye pressure due to insufficient drainage of aqueous humor, the biological fluid found at the front of the eyeball. Advances in genetic research have discovered that some inherited mutations in a gene called MYOC can eventually cause POAG. An eye structure called the trabecular meshwork is important for controlling eye pressure because it facilitates the drainage of aqueous humor. Studies have shown that some of the inherited mutations can cause myocilin to become "misfolded" into an aggregated structure that can damage the trabecular meshwork cells, leading to increased eye pressure.

A new class of therapeutic agents called pharmacological chaperones has recently emerged to treat protein misfolding disorders, which are diseases caused by the presence or accumulation of misfolded proteins. Pharmacological chaperones are chemical compounds that can correct the structure or inhibit the aggregation of the misfolded proteins by entering the cells and binding to it. Hence, the disease onset or progression may be delayed. In this project, Dr. Wing Lee and colleagues will identify pharmacological chaperones that specifically inhibit aggregation of mutant myocilin proteins, which could lead to a new type of medicine for POAG.

To identify chemical compounds that can bind to myocilin carrying a disease-causing mutation Y437H, Lee and colleagues will make use of a new screening system called the Corning EPIC®, which will allow them to measure binding between compounds and Y437H mutant myocilin proteins. A collection of 10,000 compounds will be screened with the EPIC® to identify the myocilin "binders." In addition, the researchers will test the binding candidates in trabecular meshwork cell cultures that have POAG-related symptoms caused by the Y437H myocilin mutant proteins. Only the binders that can improve the abnormal symptoms of the cells will be selected as potential pharmacological chaperones for future studies. If successful, this approach could open up a new direction of therapeutics for POAG and other protein misfolding disorders.

About the Researcher

Dr. Lee is an Assistant Professor of Neuroscience at the Mayo Clinic in Jacksonville, Florida. His work focuses on translational research related to protein misfolding diseases. Given that the aggregation of misfolded protein is a common cause of many diseases, including an inherited form of glaucoma, Lee has developed a new method to identify small molecules that can inhibit the aggregation process specific to different misfolded protein. Identification of specific aggregation inhibitors will not only increase our understanding of the disease mechanisms, it may also be used to develop new medicines to treat diseases such as primary open-angle glaucoma caused by myocilin gene mutations.