{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:15:02Z","timestamp":1790082902613,"version":"4.0.1"},"reference-count":71,"publisher":"SAGE Publications","issue":"13-14","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"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":[[2021,7]]},"abstract":"<jats:p>The wet form of age-related macular degeneration is characterized by neovascular pathologies that, if untreated, can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. Recombinant adeno-associated virus (rAAV)-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of four rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag-1 mice that lack B and T cells, increased expression of VACM1 and ICAM1 still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a 10-fold lower dose of one of the vectors that cause a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only a minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter.<\/jats:p>","DOI":"10.1089\/hum.2021.132","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T04:31:35Z","timestamp":1624941095000},"page":"649-666","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":18,"title":["Low-Dose Recombinant Adeno-Associated Virus-Mediated Inhibition of Vascular Endothelial Growth Factor Can Treat Neovascular Pathologies Without Inducing Retinal Vasculitis"],"prefix":"10.1177","volume":"32","author":[{"given":"Shun-Yun","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwen","family":"Luo","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, South China Agricultural University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneliese","family":"Malachi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihye","family":"Ko","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Viral Vector Core, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Su","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Viral Vector Core, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9565-1567","authenticated-orcid":false,"given":"Jun","family":"Xie","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Ke","sequence":"additional","affiliation":[{"name":"Chengdu Kanghong Pharmaceutical Group Co. Ltd, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Chengdu Kanghong Pharmaceutical Group Co. Ltd, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip W.L.","family":"Tai","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangping","family":"Gao","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5207-0041","authenticated-orcid":false,"given":"Claudio","family":"Punzo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA"},{"name":"Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(13)70145-1"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2016.040"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10050981"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006982-200410000-00002"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0012-9"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301203"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.586"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/104303403321070829"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301680"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.04.022"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2008.115"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.230"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.12.002"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13020219"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00345-1"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2019.03.006"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30979-0"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2020-316195"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajoc.2020.100680"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/2474126420930863"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005708"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2017.85"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.26.3075"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.020"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3303074"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182412299"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.1.309-319.1998"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070544"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-013-2392-6"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-008-9718-9"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2017.187"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1177\/0300060518819613"},{"key":"e_1_3_5_34_2","first-page":"2322","article-title":"Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression","volume":"63","author":"Dirkx AE","year":"2003","unstructured":"Dirkx AE, , Oude Egbrink MG, , Kuijpers MJ, et al. Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res, 2003; 63:2322\u20132329.","journal-title":"Cancer Res"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.2.667.bloodjournal882667"},{"key":"e_1_3_5_36_2","first-page":"1111","article-title":"Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors","volume":"56","author":"Griffioen AW","year":"1996","unstructured":"Griffioen AW, , Damen CA, , Martinotti S, et al. Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res, 1996; 56:1111\u20131117.","journal-title":"Cancer Res"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11060871"},{"key":"e_1_3_5_38_2","first-page":"095513","article-title":"viral vectors","volume":"8","author":"Sena-Esteves M","year":"2020","unstructured":"Sena-Esteves M, , Gao G, Introducing genes into mammalian cells: viral vectors. Cold Spring Harbor Protoc, 2020; 8:095513.","journal-title":"Cold Spring Harbor Protoc"},{"key":"e_1_3_5_39_2","author":"Venkatesh A","unstructured":"Venkatesh A, , Ma S, , Langellotto F, et al. Retinal gene delivery by rAAV and DNA electroporation. Curr Protoc Microbiol 2013;Chapter 14:Unit 14D 14.","journal-title":"Curr Protoc Microbiol"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2000339117"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.04.111"},{"key":"e_1_3_5_42_2","first-page":"37","article-title":"Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovasularization in monkeys","volume":"14","author":"Zhang M","year":"2008","unstructured":"Zhang M, , Zhang J, , Yan M, et al. Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovasularization in monkeys. Mol Vis, 2008; 14:37\u201349.","journal-title":"Mol Vis"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.6"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH03-02-0084"},{"key":"e_1_3_5_45_2","first-page":"101","article-title":"Oxygen-induced retinopathy in the mouse","volume":"35","author":"Smith LE","year":"1994","unstructured":"Smith LE, , Wesolowski E, , McLellan A, et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci, 1994; 35:101\u2013111.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1159\/000509380"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-13397"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-1780"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10633-009-9181-x"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.14-15067"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65157"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003554"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2012.05.012"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90030-G"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.3.905"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2015.06.003"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-4711-5_3"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1002140812979"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(93)90473-S"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22942"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00978"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.11-8353"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80297"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-8-176"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-68488-z"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21445"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.2337\/db09-1420"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129861"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1097\/IAE.0000000000001274"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-014-2717-0"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-016-2147-8"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.49890"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2021.132","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2021.132","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2021.132","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:55:42Z","timestamp":1777449342000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2021.132"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7]]},"references-count":71,"journal-issue":{"issue":"13-14","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1089\/hum.2021.132"],"URL":"https:\/\/doi.org\/10.1089\/hum.2021.132","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7]]}}}