{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T02:49:44Z","timestamp":1782787784364,"version":"3.54.5"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004080","name":"Korea Drug Development Fund","doi-asserted-by":"publisher","award":["HN22C0190"],"award-info":[{"award-number":["HN22C0190"]}],"id":[{"id":"10.13039\/501100004080","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004786","name":"Southwest Airlines","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004786","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1\u03b2 and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions.<\/jats:p>","DOI":"10.1371\/journal.pone.0305466","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T17:52:31Z","timestamp":1720720351000},"page":"e0305466","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1"],"prefix":"10.1371","volume":"19","author":[{"given":"Seo Yun","family":"Moon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Kwon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Sub","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Yoon","family":"Won","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2472-5159","authenticated-orcid":true,"given":"Steven Hyun Seung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"pone.0305466.ref001","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis","volume":"2","author":"WL Wong","year":"2014","journal-title":"Lancet Glob Health"},{"key":"pone.0305466.ref002","doi-asserted-by":"crossref","first-page":"164","DOI":"10.4103\/0974-9233.154389","article-title":"Novel pharmacotherapies in diabetic retinopathy.","volume":"22","author":"VS Dedania","year":"2015","journal-title":"Middle East Afr J Ophthalmol"},{"key":"pone.0305466.ref003","first-page":"353","article-title":"Age-related macular degeneration (AMD): pathogenesis and therapy.","volume":"58","author":"JZ Nowak","year":"2006","journal-title":"Pharmacol Rep"},{"key":"pone.0305466.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/CS20120588","article-title":"Advances in our understanding of diabetic retinopathy","volume":"125","author":"AW Stitt","year":"2013","journal-title":"Clin Sci (Lond)"},{"key":"pone.0305466.ref005","first-page":"84l","article-title":"VEGFR1 signaling in retinal angiogenesis and microinflammation.","author":"A Uemura","year":"2021","journal-title":"Prog Retin Eye Res."},{"key":"pone.0305466.ref006","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","article-title":"VEGF in signaling and disease: beyond discovery and development","volume":"176","author":"RS Apte","year":"2019","journal-title":"Cell"},{"key":"pone.0305466.ref007","doi-asserted-by":"crossref","first-page":"e71808","DOI":"10.1371\/journal.pone.0071808","article-title":"VEGF receptor blockade markedly reduces retinal microglia\/macrophage infiltration into laser-induced CNV","volume":"8","author":"H Huang","year":"2013","journal-title":"PLoS One"},{"key":"pone.0305466.ref008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00592-012-0449-3","article-title":"Pathophysiology and treatment of diabetic retinopathy.","volume":"50","author":"F Bandello","year":"2013","journal-title":"Acta Diabetol"},{"key":"pone.0305466.ref009","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1007\/s00018-016-2147-8","article-title":"Inflammation and its role in age-related macular degeneration","volume":"73","author":"A Kauppinen","year":"2016","journal-title":"Cell Mol Life Sci"},{"key":"pone.0305466.ref010","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.visres.2017.04.003","article-title":"\u2019Leary OE, Stitt AW. 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