2013 Shaffer Research Grants

Glaucoma is a leading cause of irreversible blindness affecting 70 million people worldwide. There are various types of glaucoma, and two of them can affect children and young adults: primary congenital glaucoma (PCG) and juvenile open-angle glaucoma (JOAG). PCG and JOAG are hereditary diseases that can be inherited in families. The genetic causes of PCG and JOAG partially overlap with adult-onset primary open-angle glaucoma (POAG), the most common form of glaucoma. We believe that a significant proportion of the genetic causes of POAG can be explained by genetic variants in genes that underlie PCG and JOAG. In this study we aim to identify new genetic causes of PCG and JOAG using the newest genetic technologies (exome sequencing) in families, and to evaluate the role of such new genes in POAG patients. The results of this project will improve our understanding of glaucoma, which will enable the design of new therapies.

There is a critical need to clarify the mechanisms of glaucoma at the molecular level to help provide physicians with tools for early detection and treatment. Recently, we showed that duplication of a gene (TBK1) causes some cases of a form of glaucoma that occurs at low eye pressure. Some patients have glaucoma because they carry an extra copy of TBK1 in their genome. We plan to extend this discovery by developing a model of TBK1 glaucoma that will facilitate studies of the basic mechanisms by which defects in genes cause the disease. The project may also facilitate development and testing of new sight-saving drug therapies for glaucoma.

In February 2015, Ophthalmology Times reported that Dr. Fingert’s continuing research provides strong evidence that mutation of the TBK1 gene can lead to glaucoma and may provide insights into disease mechanisms and future treatments. “Hopefully this will open up a new field for low-pressure glaucoma research and treatment,” Dr. Fingert said. He presented his research results at the 2014 meeting of American Academy of Ophthalmology.

All forms of glaucoma have in common optic nerve degeneration characterized by typical visual field defects, and are usually associated with elevated intraocular pressure, also known as ocular hypertension (OH). In most instances, OH results from impaired drainage of aqueous humor through the trabecular meshwork ™. Treatment with steroid drugs in the eye can cause OH insusceptible individuals. In preliminary studies, two newly discovered genes encoding sugary molecules called mucins were associated with steroid-induced OH. It is hypothesized that the novel mucins are part of a sugar-rich TM coating known as the glycocalyx, and that their altered production in response to steroids could lead to OH. The purpose of this project is to provide additional supporting data. Behavior of the two novel mucins will be examined in cultured TM cells and in the TM of intact eyes using recombinant DNA, biochemical, and imaging techniques in order to provide clues to function. Glycocalyces are found in all organs and play important roles in health and disease. Recent studies suggest that the glycocalyx in the outflow pathways of the eye may be much more extensive than previously imagined. The idea that mucins might be present in this lining layer and play a role in OH has not been previously considered. If confirmed, the findings will open a new line of research that could ultimately lead to significant innovation, as drugs that control amounts of the novel mucins could be a new treatment paradigm for glaucoma.

Primary open-angle glaucoma (POAG) is a leading cause of incurable blindness. Increased pressure inside the eye due to slowed fluid drainage contributes to the disease process in a majority of patients with POAG. Because some families seem to be affected more than others, inherited risk factors are suspected to play an important role in the development of glaucoma. Indeed, several genetic defects have been identified that likely contribute to the pressure increase inside the eye. In this project we intend to show that we can insert healthy copies of a damaged gene into the fluid drainage channels inside the eye and normalize eye pressure. Our project will hopefully provide proof of principle that gene therapy could one day provide lasting control of normal eye pressure in patients with known genetic defects.

For his research on the potential of gene therapy to provide lasting control of intraocular pressure in glaucoma patients with known genetic defects, András Komáromy, DVM, PhD was awarded the 2015 Shaffer Prize for Innovative Glaucoma Research. The Shaffer Prize, presented annually by the GRF Scientific Advisory Committee, recognizes a researcher whose project best exemplifies the pursuit of innovative ideas in the quest to better understand glaucoma. Dr. Komáromy studies the molecular causes of inherited eye diseases in dogs and is working to develop gene therapies to stop vision loss. By identifying and treating gene mutations in dogs, his research moves us closer to gene therapy that could one day be used to manage and prevent glaucoma in humans.

The goal of this project is to better understand the mechanisms involved in glaucomatous injury to the eye. We will study specific subtypes of cells in the eye that are more or less susceptible to glaucoma damage. Damage to the visual sensing structures in the eye and brain will be evaluated over time in order to determine onset and extent of damage. This project will help identify pathways that may serve as new targets for the development of effective glaucoma treatments. These experiments also may lead to the discovery of more sensitive ways to diagnose glaucoma and follow glaucoma progression.

A major deficit in glaucoma management is that a diagnosis is made or treatment is initiated after there is already evidence of optic nerve cell death or visual field loss. Our goal is to investigate the parts of the optic nerve cell, specifically axons and synapses, which may be vulnerable early in the course of the disease. Axons are the long projections of neurons that conduct electrical impulses, and information is transmitted from one neuron to a second neuron across the synapses located at the ends of neurons. Investigation of the effects of elevated eye pressure on the optic nerve cell axons and synapses is critical to our long-term goals of improving diagnosis and treatment for glaucoma patients. We will use a glaucoma model to study whether the gene Sarm1 plays a role in glaucoma-induced axon death and synapse loss in the retina and brain. If Sarm1 plays a role in axon or synapse loss in our model, it would be an attractive drug target for treating glaucoma. This project seeks to uncover a new approach to glaucoma diagnosis and treatment before the optic nerve is irreversibly damaged.

The debilitating loss of vision associated with advanced forms of glaucoma result directly from the degeneration of Retinal Ganglion Cells (RGC) in the retina. The pattern of RGC loss in patients as well as information obtained from laboratory research all point to the fact that an important site of pathology occurs at the optic nerve head, a region where the axonal cell processes of RGCs exit the eye on their way to the visual centers of the brain. Compressive injury associated with the elevated eye pressures in glaucoma is thought to exert a deleterious effect directly on RGC axons at this site, eventually compromising the normal biological processes required for overall RGC health, and ultimately leading to RGC death. Despite this generally well-accepted idea for how high eye pressure may affect RGC axons, scientists still do not understand the injury mechanisms involved in sufficient detail to begin identifying potential therapeutic targets. A major hurdle in elucidating the progression of axon pathology is the lack of research instrumentation to systematically map the effects of compressive injury on individual nerve cell elements. Our project will utilize two novel microscale technologies originating from our laboratory, namely highly precise molecular micropatterning and miniaturized axon nano-compressors to address this problem. Results from this study may allow us to better understand the injury threshold leading to irreversible RGC degeneration. This in turn can provide insight into the key cellular pathways that are potentially amenable for therapeutic intervention.

Glaucoma is one of the leading causes of blindness worldwide characterized by irreversible damage in the optic nerve head (ONH). Yet, the causes to the ONH damage remain unclear. One possible theory underlying the mechanism is that the blood supply to the ONH in glaucoma patients becomes insufficient due to impaired “autoregulation” capacity, an intrinsic function of a tissue to maintainconstant blood supply. However, this theory has never been conclusively proven due partially to a lack of effective methods to quantify the performance of autoregulation in the ONH. In this study, a new method to assess the performance of autoregulation in ONH is proposed. It takes advantage of spontaneous fluctuation in blood pressure (BP) and artificially induced BP change. The ultimate goal is to use the methods and analytical techniques to examine the ONH autoregulation capacity and to define the autoregulation abnormalities in glaucoma.