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Elastin is a critical component of Bruch\u2019s membrane (BrM), an ECM layer that separates the retinal pigment epithelium (RPE) from the underlying choriocapillaris. Reduced integrity of BrM\u2019s elastin layer corresponds to areas of choroidal neovascularization (CNV) in wet AMD. Serum levels of elastin-derived peptides and anti-elastin antibodies are significantly elevated in AMD patients along with the prevalence of polymorphisms of genes regulating elastin turnover. Despite these results indicating significant associations between abnormal elastin turnover and AMD, very little is known about its exact role in AMD pathogenesis. Here we report on results that suggest that elastase enzymes could play a direct role in the pathogenesis of AMD. We found significantly increased elastase activity in the retinas and RPE cells of AMD mouse models, and AMD patient-iPSC-derived RPE cells. A1AT, a protease inhibitor that inactivates elastase, reduced CNV lesion sizes in mouse models. A1AT completely inhibited elastase-induced VEGFA expression and secretion, and restored RPE monolayer integrity in ARPE-19 monolayers. A1AT also mitigated RPE thickening, an early AMD phenotype, in HTRA1 overexpressing mice, HTRA1 being a serine protease with elastase activity. Finally, in an exploratory study, examining archival records from large patient data sets, we identified an association between A1AT use, age and AMD risk. Our results suggest that repurposing A1AT may have therapeutic potential in modifying the progression to AMD.<\/jats:p>","DOI":"10.3390\/cells12091308","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T01:33:36Z","timestamp":1683164016000},"page":"1308","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exploring the Therapeutic Potential of Elastase Inhibition in Age-Related Macular Degeneration in Mouse and Human"],"prefix":"10.3390","volume":"12","author":[{"given":"Soumya","family":"Navneet","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlene","family":"Brandon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1713-0632","authenticated-orcid":false,"given":"Kit","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Healthcare Leadership and Management, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2758-3771","authenticated-orcid":false,"given":"B\u00e4rbel","family":"Rohrer","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA"},{"name":"Ralph H. Johnson VA Medical Center, Division of Research, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S1568-1637(02)00007-7","article-title":"Photoreceptor degeneration and dysfunction in aging and age-related maculopathy","volume":"1","author":"Jackson","year":"2002","journal-title":"Ageing Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/978-1-4614-3209-8_38","article-title":"A mechanistic review of cigarette smoke and age-related macular degeneration","volume":"801","author":"Woodell","year":"2014","journal-title":"Adv. Exp. Med. 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