Targeting the Immune System to Prevent Glaucoma

Meredith Gregory-Ksander, PhD
The Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary (Boston, MA)

Co-Principal Investigators

Kip M. Connor, PhD
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Glaucoma
Award Amount:
$200,000
Grant Reference ID:
G2019340
Award Type:
Standard
Award Region:
US Northeastern

Recipient of the Dr. Douglas H. Johnson Award for Glaucoma.

Meredith Gregory-Ksander, PhD

Targeting the Alternative Complement Pathway in Glaucoma

Summary

Glaucoma is a progressive eye disease that ultimately leads to the death of retinal ganglion cells (RGC) and loss of vision and recent studies have linked the progressive loss of RGCs with an over-activated immune system. In the healthy eye, inflammation is tightly regulated in order to protect the delicate tissues necessary for vision. However, in glaucoma inflammation in the eye becomes dysregulated resulting in death of RGCs and degeneration of the optic nerve. We have identified an important component of the immune system that we believe becomes dysregulated early in glaucoma and in this project we will determine the efficacy of targeting this pathway as a novel treatment for patients with glaucoma.

Details

Accumulating evidence from both human and animal models of glaucoma implicates inflammation as a key driver of retinal ganglion cell death and optic nerve degeneration, In this project we will test a promising new treatment strategy that targets the complement pathway, an important component of inflammation that we recently identified as a key mediator of retinal ganglion cell death in an experimental model of glaucoma.

The complement system can be activated through three different pathways either: the classical pathway, the lectin pathway, or the alternative pathway. Aim 1 of this project will use an inducible mouse model of glaucoma in conjunction with two different knockout-mouse strains in which the classical or alternative pathway has been inactivated. These studies will determine the relative importance of these two complement pathways in the development of glaucoma. In Aim 2 we will use specific inhibitors to block the most important complement pathway identified in Aim 1 and determine whether this prevents the development of glaucoma. In addition, we will determine whether the inhibitors can still provide significant protection when administered after glaucoma has already started.

The successful completion of this project will identify the complement pathway that is required for the development of glaucoma and demonstrate that blocking this pathway may be a new therapeutic approach for treating glaucoma patients.

About the Researcher

Meredith Gregory-Ksander is an Associate Scientist at The Schepens Eye Research Institute, Massachusetts Eye and Ear and Assistant professor in the Department of Ophthalmology, Harvard Medical School. Dr. Gregory-Ksander received her Ph.D. in Cell Biology, Neurobiology and Anatomy from Loyola University of Chicago in 1999 and completed a Postdoctoral Fellowship at Schepens Eye Research Institute before joining the faculty at The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School in 2004. The research in Dr. Gregory-Ksander’s laboratory is focused on understanding the molecular mechanism(s) of RGC death in glaucoma, with the goal of preventing RGC death and preserving vision. With an expertise in cell biology and immunology, Dr. Gregory-Ksander has had a longstanding interest in how age-related changes in ocular immune privilege and subsequent inflammation contributes to the development of glaucoma. While the importance of inflammation in glaucoma is now recognized in the field of glaucoma, how it is triggered in and how it is controlled is largely unknown. Using multiple experimental models of glaucoma, Dr. Gregory-Ksander is working to identify the key inflammatory pathways involved in the pathogenesis of glaucoma in order to (i) elucidate the mechanism(s) by which inflammation contributes to the development of and/or progression of glaucoma and (ii) identify novel targets for the development of new therapeutics that will protect the retinal ganglion cells, prevent axon degeneration, and preserve vision in all types of glaucoma patients, irrespective of the intraocular pressure.

Personal Story

 Glaucoma causes the loss of vision by destruction of specific neurons in the retina called retinal ganglion cells and this may coincide with an increase in the pressure within the eye. Currently, the only treatment for glaucoma is to use medications or surgery that reduce the pressure within the eye. However, while these pressure-lowering therapies can slow disease progression in some patients, they fail to stop the disease from continuing. This has prompted research into intraocular pressure-independent strategies that protect the retinal ganglion cells (called neuroprotection) and preserve vision in all glaucoma patients irrespective of the pressure within the eye. Over the past decade, several neuroprotective strategies have been tested in animal models of glaucoma and, while many of these therapies were successful in these studies, they failed to translate into successful clinical treatments for patients. Thus, new and innovative approaches are necessary to develop new treatments for glaucoma and The Bright Focus Foundation has been an ardent supporter of new and innovative ideas, encouraging scientists to think outside-the-box and ask novel questions.

With this in mind, I recently started a new collaboration with the Co-PI on this project, Dr. Connor, who is an expert in complement-mediated ocular inflammation.  The complement system is a vital part of the immune system that defends against bacterial and viral infections, but over activation of the complement system has also been implicated in glaucoma. While the complement system can be activated through three different pathways, our early investigations in collaboration with Dr. Connor suggest the “alternative complement pathway”, a pathway that has not yet been studied in glaucoma, may play an important role in mediating the death of retinal ganglion cells during glaucoma. Through the generous support of BrightFocus Foundation we have now received funds to expand these studies and determine whether the alternative complement pathway is critical in the development of glaucoma and whether complement-inhibiting therapeutics can be used to prevent glaucoma.

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