Exploring Natural Immunity in Retinal Neovascular Disease

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Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the world. The number of people with AMD has reached 196 million, with ~1 in 10 people over 55 years already showing early signs of the condition. 70% of those who progress to late-stage disease will develop neovascular (nv)AMD due to uncontrolled growth of blood vessels behind the retina. In fact, aberrant growth of retinal or choroidal vasculature is a hallmark of diabetic retinopathy and nvAMD. Collectively, these are the most common causes of central vision loss globally. Identification of new biological processes that regulate neovascularization are urgently needed to open new therapeutic options for patients. This is a challenge; but with recent longitudinal studies showing unequivocally that current gold-standard care has a therapeutic ceiling, it presents a critical unmet clinical need. I have recently discovered that natural killer cells (NKs) are found in neovascular lesions in human AMD and our mouse model data suggests that these innate lymphoid cells (ILCs) play a role in inhibiting pathology. Using scRNAsequencing I discovered a defined subset of NKs in neovascular lesions in a model of resolving nvAMD. I now hypothesize that, in contrast to expectations, these ILCs play a critical role in remodelling neovascular lesions, limiting pathology as opposed to exacerbating it. NK cells are completely unstudied in the retina. Here, I propose that manipulating NK cells may represent a novel therapeutic strategy for the prevention and treatment of neovascular eye disease. Objectives: 1) Examine NK cell function in models of retinal neovascular disease 2) Profile NK cells in AMD pathology in a human study 3) Develop microfluidic “neovascular retina-on-a-chip” model to examine NK cell mechanism-of-action 4) Determine if NK cell therapy can ameliorate neovascular eye disease Goal: To harness the power of NK cell activity to treat neovascular eye diseases