Bcl-2, Subretinal Scar Formation and Neovascular AMD

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PROJECT SUMMARY Age-related macular degeneration (AMD) is a progressive and neurodegenerative disease that affects individuals typically over the age of 60 leading to vision loss. Inflammation is increasingly recognized as an important modulator driving choroidal neovascularization (CNV) and subretinal scar formation in neovascular AMD (nAMD). Although great effort has been given to understanding how to curtail CNV, less is known regarding the initiation and persistence of fibrosis and subretinal scars. Unfortunately, at least 1/3 of nAMD patients develop subretinal scars, which are typically associated with unsuccessful anti-VEGF treatment outcomes. The interrelationship between inflammation, fibrosis, CNV, their termination and the processes involved is not well defined. We have shown the important role Bcl-2 family members play in these processes. Bcl-2 is an anti-apoptotic Bcl-2 family member that prolongs inflammation. Mononuclear phagocytes (MP) play essential roles in choroidal inflammation, neovascularization, and subretinal scar formation. Our hypothesis is that unbridled Bcl-2 expression in MP prolongs inflammation resulting in enhanced subretinal fibrosis and scar formation. Extending cell lifespan, through increased Bcl-2 expression, has a well-documented negative impact on tissue homeostasis. In this proposal we will take the innovative approach of determining whether Bcl-2 expression in MP sustains inflammation leading to CNV, subretinal fibrosis and scar formation. Furthermore, we will utilize several approaches to block Bcl-2 function and increase apoptosis including the FDA approved Venetoclax (ABT-199), which has been successfully used to treat cancer. The aims proposed here will determine the extent to which Bcl-2 expression in MP drives persistent fibrosis and subretinal scar formation following laser photocoagulation mediated CNV. We will examine its impact on inflammation, CNV, subretinal fibrosis and scar formation and regression when treated with Bcl-2 inhibitors, such as the FDA approved ABT-199. Delineating the fundamental role Bcl-2 plays in modulating inflammation and subsequent fibrosis and subretinal scar formation will allow to greatly improve vision outcomes in patients with nAMD.