Dr. Jon Houtman, Professor and Vice Chair in the Department of Microbiology and Immunology is part of a Multi-PI team, in collaboration with Dr. Elliott Sohn (contact PI) Associate Professor of Opthalmology and Visual Science and Dr. Milan Sonka, Professor of Electrical & Computer Engineering, to be awarded a 4-year $3 million National Institutes of Health/National Eye Institute R01 Research Grant titled, “MMP-9 based immune-driven mechanisms of neovascular AMD.” Most patients with neovascular age-related macular degeneration (AMD) need eye injections every 1-3 months for the remainder of their lives. This study will contribute to our understanding of a novel immune-mediated mechanism involved in neovascular AMD that is associated with incomplete response to treatment.

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.