MMP-9 based immune-driven mechanisms of neovascular AMD

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PROJECT SUMMARY/ABSTRACT The neovascular ‘wet’ form of age-related macular degeneration (nvAMD), whereby new blood vessels grow under the retina, requires treatment with anti-vascular endothelial growth factor eye injections typically every 1- 3 months for the remainder of patients’ lives due to persistent fluid, which can be visualized and quantified by optical coherence tomography (OCT) imaging. Recent research has implicated matrix metalloproteinase 9 (MMP9), expressed in immune cells of the retinal blood supply (termed choroid), as a mediator in the formation and persistence of nvAMD. This proposal will elucidate our understanding of this novel immune-based mechanism. Characteristics of patients with high-risk genotype of MMP9 will also be assessed, as they are associated with incomplete response to standard therapies for nvAMD. We will identify genetic regulatory regions that control expression of MMP9 and determine the immunologic activation profiles in patients with nvAMD. We will use artificial intelligence (AI)-based approaches to associate phenotypic features observable on OCT and OCT-angiography with high- and low-risk MMP9 genotypes in patients with nvAMD. Our outstanding team of interdisciplinary researchers will collaborate to employ state-of-the-art genomic and immunologic techniques to study the mechanisms of how MMP9 is implicated in nvAMD and fibrosis. Genetics will aid AI- and machine learning-based analysis of OCT images to learn new features associated with the most challenging patients afflicted with nvAMD. Unraveling the disease mechanisms associated with MMP9 will reveal new targets for therapeutic intervention. This proposal encompasses 5 of the 7 cross-cutting areas of emphasis the NEI laid out in the 5-year Strategic Plan on November 1, 2021. This is the next, necessary milestone in nvAMD that will help to address this major socioeconomic health burden.