{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T20:50:57Z","timestamp":1777668657239,"version":"3.51.4"},"reference-count":69,"publisher":"SAGE Publications","issue":"19-20","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:p>\n                    Corneal neovascularization (CoNV) is both a sight-threatening condition in and of itself and a major risk factor associated with corneal graft failure. Here, we determine the effectiveness of an adeno-associated viral vector (AAV)-based gene therapy targeting both hematic and lymphatic neovascularization in a murine model of severe CoNV. We first assessed the profile of transgene expression mediated by intrastromal injection of AAV2\/8[Y733F] via longitudinal visualization of an enhanced Green Fluorescent Protein (eGFP) transgene and found that this serotype mediates a temporary (\u223c18 day) transduction of the corneal epithelium and sustained (\u2265148 day) transduction within the stroma. Constitutively expressed\n                    <jats:italic toggle=\"yes\">sFlt1<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">sFlt4<\/jats:italic>\n                    were prophylactically delivered via intrastromal injection of AAV2\/8[Y733F] vector at various intervals prior to aggressive induction of CoNV in a murine model. The extent of CoNV induced was quantified by fluorescein angiography and immunohistochemistry 17 days after induction. AAV2\/8[Y733F]-CMV-sFlt1 was highly effective in the prevention of hemangiogenesis (HA) induced at 3, 28, and 210 days after intrastromal injection, but ineffective in the prevention of lymphangiogenesis. Two variants of AAV2\/8[Y733F]-CMV-sFlt4 were ineffective in the prevention of angiogenesis when delivered alone, but combined delivery of AAV2\/8[Y733F]-CMV-sFlt1 and AAV2\/8[Y733F]-CMV-sFlt4 suggested a synergistic effect. Our results show that a single intrastromal injection of AAV2\/8[Y733F]-CMV-sFlt1 is sufficient to protect against a robust stimulus for corneal HA over the long term. This technique could also be applied\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    to reduce the risk of failure in cases of \u201chigh-risk\u201d corneal transplantation.\n                  <\/jats:p>","DOI":"10.1089\/hum.2024.248","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T04:31:20Z","timestamp":1748406680000},"page":"1331-1345","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Stromal Gene Therapy Mediates Prolonged Protection Against Corneal Neovascularization Induced by an Aggressive Angiogenic Insult"],"prefix":"10.1177","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9861-6888","authenticated-orcid":false,"given":"Mark","family":"Basche","sequence":"first","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, King\u2019s College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Robbie","sequence":"additional","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, King\u2019s College London, London, UK"},{"name":"Department of Ophthalmology, Guy\u2019s &amp; St. Thomas\u2019 Hospitals NHS Foundation Trust, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. Frank P.","family":"Larkin","sequence":"additional","affiliation":[{"name":"NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, King\u2019s College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael A.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, King\u2019s College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin R.","family":"Ali","sequence":"additional","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, King\u2019s College London, London, UK"},{"name":"UCL Institute of Ophthalmology, London, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00055735-200108000-00002"},{"issue":"2","key":"e_1_3_6_3_2","first-page":"198","article-title":"Corneal transparency: Genesis, maintenance and dysfunction","volume":"81","author":"Ljubimov AV","year":"2010","unstructured":"Ljubimov AV, , Qazi Y, , Wong G, et al. Corneal transparency: Genesis, maintenance and dysfunction. Brain Res Bull, 2010; 81(2):198\u2013210.","journal-title":"Brain Res Bull"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2011.246"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05249"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-453043"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1442-9071.2007.01549.x"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2006.05.001"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2006.09.001"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23298"},{"issue":"9","key":"e_1_3_6_11_2","first-page":"2514","article-title":"Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas","volume":"41","author":"Philipp W","year":"2000","unstructured":"Philipp W, , Speicher L, , Humpel C. Expression of vascular endothelial growth factor and its receptors in inflamed and vascularized human corneas. Invest Ophthalmol Vis Sci, 2000; 41(9):2514\u20132522.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2012.03.018"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2009.05.009"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000099253"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.3109\/08830185.2012.737877"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-6420(94)31138-9"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e3181903b0a"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2008.305"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2010.01.039"},{"issue":"12","key":"e_1_3_6_20_2","first-page":"2485","article-title":"Loss and restoration of immune privilege in eyes with corneal neovascularization","volume":"37","author":"Dana M","year":"1996","unstructured":"Dana M, , Streilein J. Loss and restoration of immune privilege in eyes with corneal neovascularization. Invest Ophthalmol Vis Sci, 1996; 37(12):2485\u20132494.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/ACI.0b013e32833dfa11"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903180"},{"key":"e_1_3_6_23_2","first-page":"1694","article-title":"Clinicopathological correlation analysis of (lymph) angiogenesis and corneal graft rejection","volume":"17","author":"Zheng Y","year":"2011","unstructured":"Zheng Y, , Lin H, , Ling S. Clinicopathological correlation analysis of (lymph) angiogenesis and corneal graft rejection. Mol Vis, 2011; 17:1694\u20131700.","journal-title":"Mol Vis"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2018"},{"issue":"8","key":"e_1_3_6_25_2","first-page":"2148","article-title":"Fine needle diathermy occlusion of corneal vessels","volume":"41","author":"Pillai CT","year":"2000","unstructured":"Pillai CT, , Dua HS, , Hossain P. Fine needle diathermy occlusion of corneal vessels. Invest Ophthalmol Vis Sci, 2000; 41(8):2148\u20132153.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2003.035071"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1097\/ICO.0000000000002406"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.survophthal.2012.01.007"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.126.1.71"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2012-302137"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/HGTB.2011.034"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.359"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.115"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021244"},{"issue":"8","key":"e_1_3_6_36_2","first-page":"1757","article-title":"Integrity of epithelium and endothelium in organ-cultured human corneas","volume":"42","author":"Crewe JM","year":"2001","unstructured":"Crewe JM, , Armitage WJ. Integrity of epithelium and endothelium in organ-cultured human corneas. Invest Ophthalmol Vis Sci, 2001; 42(8):1757\u20131761.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000000512"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035318"},{"issue":"3","key":"e_1_3_6_39_2","first-page":"751","article-title":"Inducible adeno-associated virus vector-delivered transgene expression in corneal endothelium","volume":"43","author":"Tsai M-L","year":"2002","unstructured":"Tsai M-L, , Chen S-L, , Chou P-I, et al. Inducible adeno-associated virus vector-delivered transgene expression in corneal endothelium. Invest Ophthalmol Vis Sci, 2002; 43(3):751\u2013757.","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"4","key":"e_1_3_6_40_2","first-page":"983","article-title":"Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis - PubMed","volume":"27","author":"Goater J","year":"2000","unstructured":"Goater J, , M\u00fcller R, , Kollias G, et al. Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis - PubMed. J Rheumatol, 2000; 27(4):983\u2013989.","journal-title":"J Rheumatol"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-007-0683-5"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-014-2749-5"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.11-8391"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1167\/IOVS.02-0299"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1076\/0271-3683(200007)2111-ZFT550"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090794"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-01-066811"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1182\/BLOOD-2010-02-267427"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20465"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1911"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.87"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303215"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71603"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40883-018-0054-2"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/EMBOJ.2011.456\/SUPPL_FILE\/EMBJ2011456.REVIEWER_COMMENTS.PDF"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1042\/cs20040370"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1083\/JCB.200409115"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.OMTM.2021.06.007"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1089\/104303401750270959"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301695"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11373-007-9153-7"},{"key":"e_1_3_6_62_2","first-page":"2344","article-title":"Subconjunctival injection of recombinant AAV-angiostatin ameliorates alkali burn induced corneal angiogenesis","volume":"13","author":"Cheng H-C","year":"2007","unstructured":"Cheng H-C, , Yeh S-I, , Tsao Y-P, et al. Subconjunctival injection of recombinant AAV-angiostatin ameliorates alkali burn induced corneal angiogenesis. Mol Vis, 2007; 13:2344\u20132352.","journal-title":"Mol Vis"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302769"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026432"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/S41598-017-18002-9"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.OMTN.2017.12.019"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.07.114"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.YMTHE.2019.12.010"},{"key":"e_1_3_6_69_2","first-page":"1760","article-title":"Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential","volume":"14","author":"Li Q","year":"2008","unstructured":"Li Q, , Miller R, , Han P-Y, et al. Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis, 2008; 14:1760\u20131769.","journal-title":"Mol Vis"},{"key":"e_1_3_6_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.YMTHE.2025.01.028"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2024.248","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2024.248","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2024.248","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:50:46Z","timestamp":1777449046000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2024.248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":69,"journal-issue":{"issue":"19-20","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1089\/hum.2024.248"],"URL":"https:\/\/doi.org\/10.1089\/hum.2024.248","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]}}}