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.

Project 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.