Evaluating Mechanisms and Therapeutic Potential of (GLP-1R) Agonists for Glaucoma Treatment

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Project Summary Glaucoma is characterized by retinal ganglion cell (RGC) death leading to vision loss. Available treatment modalities continue to rely on intraocular pressure (IOP) reduction, which is insufficient to prevent progressive neurodegeneration in a significant number of glaucoma patients. In the fight against this blinding disease, treatment strategies that do not rely on IOP-lowering are urgently needed. In this proposal, we hypothesize that glucagon-like peptide-1 receptor (GLP-1R) agonists protect against glaucomatous neurodegeneration by decreasing microglia/macrophage activation and retinal macrophage infiltration, in turn preventing reactive astrogliosis resulting in RGC rescue. This hypothesis builds upon our prior study showing that induced ocular hypertension in a mouse model of glaucoma triggers microglia/macrophage activation and reactive astrocyte formation in the retina. We found that treatment with the long-acting GLP-1R agonist NLY01 suppressed microglia/macrophage activation, prevented reactive astrogliosis, and rescued RGCs following IOP elevation. Further, our examination of insurance claims data showed that treatment with GLP-1R agonists, FDA-approved to treat diabetes and for weight loss, is associated with decreased glaucoma risk in humans. However, the retinal cell type(s) mediating GLP-1R agonists' RGC protection have not been identified. Further, it is not known whether systemic macrophage infiltration and/or resident microglia transformation drive early inflammation, and whether NLY01 modifies this response. Finally, whether this favorable response to NLY01 treatment generalizes beyond induced IOP elevation to inherited models of chronic, progressive glaucoma is unknown. This proposal will pursue 2 specific aims crucial to evaluating GLP-1R agonists' mechanism of action and the potential GLP-1R agonists hold as novel glaucoma therapy: 1) Determine the mechanisms through which the GLP-1R agonist NLY01 rescues RGCs following IOP elevation, and 2) Determine the mechanisms of GLP-1R agonist-mediated neural rescue in an inherited model of glaucoma. Findings will determine: 1) the systemic cell type(s) facilitating NLY01's RGC rescue, including whether macrophage infiltration drives early inflammation in response to ocular hypertension, and 2) whether the GLP-1R agonist NLY01 exerts a long-term anti-inflammatory effect to rescue RGCs in the DBA/2J mouse model of glaucoma. This proposal is the first step in a broader plan to disentangle systemic effects of GLP-1R activation driving neuronal rescue. Results will serve to advance our understanding of glaucoma pathogenesis, identify the mechanisms driving NLY01-mediated RGC rescue, and elucidate the potential for using GLP-1R agonists in glaucoma treatment.