Glaucoma Research Program
Glaucoma is a group of eye diseases characterized by vision loss due to damage of the optic nerve. Over 60 million people worldwide are affected by the disease. A medical finding of increased pressure in the front of the eye, referred to as elevated intraocular pressure, is a common risk factor for the disease. If left untreated, vision loss may occur eventually leading to blindness.
The mission of the Mayo Clinic Glaucoma Research Program is to understand the unique functions of the normal eye, to determine the changes associated with normal and elevated intraocular pressure, to learn the natural history of this blinding disease, and to develop and assess existing and new therapies to combat glaucoma. We accomplish these goals through laboratory and clinical research.
- Unlocking the Cause of Glaucoma. Intraocular pressure is a dynamic parameter that varies randomly as well as with a circadian rhythm. In most glaucomas, elevated intraocular pressure occurs due to changes in the trabecular meshwork, the tissue mainly responsible for draining the internal fluid of the eye (aqueous humor). Eventually, the high pressure damages the optic nerve and can result in blindness if not treated. Glaucoma is treated by reducing the eye pressure, through medicine (eye drops) or eye surgery, although these treatments are not effective in all cases. Our research focuses on understanding why intraocular pressure is higher in glaucoma patients, why intraocular pressure variations occur in normal and glaucoma patients, new surgical procedures to reduce intraocular pressure, and the effectiveness of various long-term treatments of this disease.
- Develop Pioneering Methods to Treat Glaucoma. The effective treatment of chronic disease such as glaucoma requires finding a therapy that can work for many years with a simple application. New procedures involving pioneering surgical treatments are being tested to increase fluid-flow through the drainage tissues of the eye. Our molecular studies are geared toward identifying molecules that are responsible for changing the normal eye condition into glaucoma. Identification of novel gene candidates may enable placement of therapeutic genes into the diseased tissue, allowing long-term, regulated expression. A recent collaboration between the department of Molecular Medicine (gene therapy) and the Glaucoma Research Laboratory has resulted in the successful insertion and activation of a gene in the living cat eye. This method overcomes the common problems of gene activity loss, immune reaction, or rejection that have frustrated other researchers. Our continued collaboration with the molecular medicine laboratory will be essential to push this promising therapy forward.
- Effectiveness of Treatments and Outcomes of Diseases. Our study of glaucoma outcomes is accomplished using a variety of clinical investigation techniques, including case series data, prospective epidemiologic studies, and study of the physiology of normal and glaucomatous volunteers. Use of the Rochester Epidemiology Project, a unique resource at the Mayo Clinic, has provided information for numerous studies on the outcome of glaucoma and the effectiveness of various treatments.
Dr. Michael Fautsch is an associate professor of Ophthalmology at the Mayo Clinic in Rochester, MN. He is a molecular biologist with an active basic science research laboratory probing the pathogenesis of glaucoma. He has two grant awards from the National Institutes of Health to study molecular and cellular aspects of normal and glaucoma eyes. His work involves culture of human eyes, histologic study of glaucomatous eyes, biologic studies of the trabecular meshwork and aqueous humor, molecular analysis of the glaucoma-associated protein myocilin, and epidemiology and clinical outcomes of glaucoma treatment. He is an expert in the culture of cells from the drainage tissues of the eye, and uses them to probe the genetic secrets of glaucoma.
Selected research efforts include:
- Pressure-Lowering Therapeutics and Molecular Changes to the Trabecular Meshwork
Using a perfusion model of human anterior segments, we have confirmed that latanoprost; a prostaglandin analogue used in the treatment of glaucoma, has a direct effect on the cells of the trabecular meshwork. We are interested in determining the molecular factors that are involved in lowering pressure by latanoprost. We are currently studying other prostaglandin analogues to determine if each therapeutic uses a unique pathway or a common pathway to lower pressure within the eye. The perfusion culture system for anterior segments is the only model to study aspects of aqueous drainage through the trabecular meshwork in the human eye.
- Aqueous Humor Flow through the Human Eye
Aqueous humor normally flows from the front part of the eye through the trabecular meshwork into a tube-like structure called Schlemm’s canal. From the canal, aqueous humor flows into smaller outflow structures called collector channels that eventually drain into the venous system. We have found that fluid flow through the trabecular meshwork is not uniform but is increased in regions of the trabecular meshwork underneath the collector channels. Anatomical differences have been identified in regions of the trabecular meshwork directly below the collector channels when compared to other regions of the trabecular meshwork. We are exploring changes in the extracellular matrix as well as the composition of the elastin fibers in these anatomically different regions. Size and shape of collector channels are also being compared in normal and glaucoma eyes.
- Functional Analysis of the Glaucoma-Associated Protein Myocilin
Myocilin was identified as a gene with a genetic link to several forms of glaucoma, including juvenile and primary open angle glaucoma. We have found that myocilin levels are elevated in the aqueous humor isolated from patients with primary open angle glaucoma and that infusion of normal recombinant myocilin protein in the perfusion culture of anterior segments can increase pressure in the eye. The function of myocilin is unknown, but determining what proteins are associated with myocilin will help in identifying its role in aqueous drainage tissues. We have developed a panel of myocilin monoclonal antibodies that will help delineate the binding partners as well as clarify myocilin localization within the human anterior segment.
- Development of an Artificial Aqueous Humor
Aqueous humor is the nutritional source for many tissues of the anterior part of the eye, including the trabecular meshwork. Two model systems exist for studying the human drainage pathway in humans: monolayer trabecular cells and the perfusion culture system for anterior segments. Neither model uses aqueous humor. We have identified significant changes in cell morphology, gene expression, and protein production in monolayer trabecular cells incubated with human aqueous humor compared to the standard culture media. We are interested in developing an artificial aqueous supplement that can be used in human culture models that will make these models similar to conditions found in the living eye.
Dr. Arthur Sit is an assistant professor of Ophthalmology at the Mayo Clinic in Rochester, MN. He is a clinician-scientist with a Master’s degree in mechanical engineering from MIT where he investigated the hydrodynamics of aqueous humor outflow. His clinical practice is focused on sub-specialty glaucoma. His current research efforts are focused on measuring and studying the circadian (24-hour) changes in intraocular pressure that occur in both glaucoma and normal patients, and what impact this may have on glaucoma progression.
Current research efforts include:
- Circadian Changes in Aqueous Humor Dynamics
Intraocular pressure (IOP) is known to vary throughout the day and night with the highest pressures occurring during sleep. This trend occurs in both normal and glaucoma patients. The reasons that these changes occur are unclear. Previous work performed at the Mayo Clinic show that the rate of production of aqueous humor (the fluid inside the eye) decreases at night. This would seem to produce a lower pressure during sleep, in contrast to what has been measured in sleep laboratories. We are currently investigating the circadian changes in the factors that contribute to intraocular pressure, including aqueous flow rate, episcleral venous pressure, outflow facility, and uveoscleral flow. As part of our efforts to characterize the circadian variations in aqueous humor dynamics, we are also developing new methods of measuring these parameters. Understanding these changes is important for the development and evaluation of glaucoma treatments, including medication, laser, and surgery.
- Development of a Non-Invasive 24-Hour Intraocular Pressure Monitor
Intraocular pressure (IOP) is the primary risk factor in glaucoma, and lowering of IOP is the only effective treatment for glaucoma at this time. However, with current technology, IOP can only be practically measured while patients are in clinic, and routine clinical practice involves measurements only a few times a year. Mounting evidence indicates that this approach is inadequate for optimal management of glaucoma since IOP varies with random fluctuations as well as a circadian rhythm with peak IOP occurring during the sleeping hours. Our current research focuses on the development of the technology required to non-invasively measure 24-hour IOPs easily and inexpensively while allowing patients to continue with normal daily activities.
- Epidemiology Studies
Epidemiological studies of glaucoma in Olmsted County are ongoing, utilizing the Rochester Epidemiology Project. Current studies include an update of the incidence of open-angle glaucoma, and an investigation into the relationship between glaucoma and sleep apnea in Olmsted County.
- Evaluation of Novel Surgical Devices
We are currently utilizing novel surgical therapies for glaucoma that eliminate many of the risks associated with traditional glaucoma surgery. The optimal parameters for these surgeries are being investigated.