The NLRP3 Inflammasome as a New Target in Glaucoma
It is believed that glaucoma develops when a part of the eye containing nerves (the optic nerve head) is stressed and damaged. Inflammation is part of the body’s wound healing response to injury, but if this response becomes chronic it can lead to scarring and loss of function. Our project identifies an important new regulator of inflammation in the optic nerve head and tests whether inhibiting this regulator will stop disease development and vision loss.
A major risk factor in glaucoma is elevated intraocular pressure (IOP) and current therapies are aimed at lowering IOP through pressure lowering medications and/or surgical intervention. While these current therapies can slow the disease progression in many patients, other patients continue to progress. Moreover, there are many glaucoma patients that never present with elevated IOPs, indicating that IOP-independent mechanisms also participate in the development of glaucoma. Recent evidence demonstrates that the initial injury in glaucoma occurs in the optic nerve head (ONH), where axon bundles exit the eye, and that activated astrocytes produce mediators that damage these axons and trigger inflammatory cell recruitment. We recently discovered that ONH astrocytes in human and mouse eyes constitutively express a critical regulator of inflammation called the NLRP3 inflammasome. Our preliminary data demonstrate triggering the inflammasome in the ONH activates inflammation that leads to the development of glaucoma.
We hypothesize that activation of the NLRP3 inflammasome in ONH astrocytes initiates inflammation and axonal damage in glaucoma. We are testing this hypothesis in two specific aims: Aim 1- Demonstrate that NLRP3 inflammasome activation is required to initiate and amplify inflammation in the ONH, resulting in the production of proinflammatory cytokines, infiltration of immune cells, production of neurotoxic mediators, axonal damage, and death of RGCs. In these studies we will elevate the IOP in genetically modified mice that do not express the NLRP3 inflammasome to demonstrate that activation of the NLRP3 inflammasome is required for (i) loss of axons and RGCs following elevated IOP, and (ii) the production of proinflammatory cytokines, infiltration of macrophages, and release of neurotoxic mediators is inhibited in NLRP3 KO mice, even in the presence of elevated IOP. Aim 2- Determine whether using a small molecule inhibitor to specifically inhibit NLRP3-driven inflammation prevents development of IOP-induced glaucoma by blocking the initiation and amplification of inflammation in the ONH. In these studies we will use a newly developed small molecule inhibitor of NLRP3, to determine (i) if we can specifically block IOP-induced NLRP3 inflammasome activation in the ONH and prevent axonal damage and death of RGCs, and (ii) how late in disease treatment with this novel inhibitor can be initiated and still provide protection for RGCs and their axons.
Upon completion, this work will provide the first evidence that the NLRP3 inflammasome contributes to the development of glaucoma by initiating inflammation in the ONH. More important, this research will serve as a pre-clinical study demonstrating the ability of this small molecule inhibitor to specifically target and inhibit NLRP3-driven inflammation and prevent the development of glaucoma, even in the presence of elevated IOP.
About the Researcher
Meredith Gregory-Ksander, PhD, is an associate scientist at Schepens Eye Research Institute, and assistant professor in the Department of Ophthalmology, Harvard Medical School. Dr. Gregory-Ksander received her PhD in Cell Biology, Neurobiology and Anatomy from the Loyola University of Chicago in 1999 and completed a postdoctoral fellowship at Schepens Eye Research Institute before joining the faculty at Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School in 2004. With an expertise in cell biology and immunology, Dr. Gregory-Ksander has had a longstanding interest in how age-related changes in immune privilege and subsequent inflammation contribute to the development of glaucoma. Her laboratory has worked with several mouse models of glaucoma, including the pigmentary dispersion model in DBA/2J mice, TNFα inducible model, open angle glaucoma model in SGC a1-deficient mice, and most recently the microbead occlusion model. Dr. Gregory-Ksander has identified two critical mediators of ocular inflammation during the development of glaucoma, Fas ligand and the NLRP3 inflammasome. Current studies in her laboratory focus on how these molecules mediate protective immunity and immune privilege in the eye and how age-related changes in these molecules may contribute to the development of glaucoma.
As a basic researcher, I do not work directly with glaucoma patients. However, I think it is very important to meet these patients to truly understand the impact that glaucoma has on their daily lives. Over the years, I have had the pleasure of giving presentations to members of the community and in particular, members of the Association for the Blind and Visually Impaired here in Massachusetts. It is through these presentations, where I have met people who suffer from glaucoma and listened to their stories of how this disease has affected them and their families, that really reinforces the importance of our research. More recently my own father was diagnosed with glaucoma, which brought the reality of this disease and how many people it effects even closer to home. Currently, the only treatment for glaucoma is the use of medications or surgery to reduce the pressure within the eye. While these pressure-lowering therapies can slow the disease progression in many patients, other patients continue to progress and lose vision. Therefore, it is clear that new avenues of intervention are needed, that are not related to the regulation of eye pressure. Our laboratory has identified a pathway that mediates damage to the optic nerve that occurs during the development of glaucoma. The generous support provided by Bright Focus Foundation will allow us to test novel drugs to determine if blocking this pathways will stop the development of glaucoma and loss of vision. The ultimate goal is to develop a new treatment that protects the optic nerve and preserves vision for all glaucoma patients, irrespective of eye pressure.
First published on: July 19, 2016
Last modified on: July 24, 2018