{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:17Z","timestamp":1790189957694,"version":"4.1.0"},"reference-count":45,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"868","funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["D-21\/SPP\/3732"],"award-info":[{"award-number":["D-21\/SPP\/3732"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["21\/RC\/10294"],"award-info":[{"award-number":["21\/RC\/10294"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101034252"],"award-info":[{"award-number":["101034252"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,9,23]]},"abstract":"<jats:p>\n                    Nonproliferative diabetic retinopathy (NPDR) is a serious and vision-threatening manifestation of diabetic eye disease. Most patients with diabetic eye disease have NPDR. Intravitreal vascular endothelial growth factor (VEGF)\u2013neutralizing agents are able to suppress increased vascular leakage caused by poor glycemic control and are fundamental in controlling progression to vision loss. However, despite the efficacy of such treatments, the invasive nature and short interval between injections have not yielded widespread adoption in patients with NPDR. Here, we describe the effect of an orally available medication, danegaptide, in regulating retinal vascular permeability in preclinical animal models of disease and report safety and early efficacy data from an early-stage phase 1b clinical trial in patients with NPDR and mild center-involved macular edema. As an orally available gap junction modifier, danegaptide improved inner blood-retina barrier (iBRB) function through a direct connexin-43 mechanism and by working as a functional antagonist of VEGF in human retinal microvascular endothelial cells. Bulk RNA sequencing showed that danegaptide attenuated the VEGF-induced suppression of\n                    <jats:italic toggle=\"yes\">TNFSF15<\/jats:italic>\n                    , an endogenous antagonist of VEGF activity in human retinal microvascular endothelial cells. In addition, targeted suppression of TNFSF15 using small interfering RNA or inhibition of its activity using a neutralizing antibody prevented VEGF-induced permeability in vitro and neovascular lesion development in vivo. No serious adverse events related to oral danegaptide were found in an early-stage phase 1b clinical trial in 24 patients with NPDR and mild center-involved macular edema. These findings support larger clinical trials to test efficacy.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aed8692","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:00:29Z","timestamp":1790186429000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical and clinical evaluation of systemic danegaptide for the treatment of nonproliferative diabetic retinopathy"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9163-8779","authenticated-orcid":true,"given":"Natalie","family":"Hudson","sequence":"first","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-0479","authenticated-orcid":true,"given":"Gerg\u0151","family":"Porkol\u00e1b","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."},{"name":"FutureNeuro Research Ireland Centre, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8818-4331","authenticated-orcid":true,"given":"Jeffrey","family":"O\u2019Callaghan","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1451-3803","authenticated-orcid":true,"given":"Nicole","family":"Hanley","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basma","family":"Baccouche","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rk","family":"Varr\u00f3","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1277-739X","authenticated-orcid":true,"given":"Ulrik","family":"Mouritzen","sequence":"additional","affiliation":[{"name":"Breye Therapeutics, 2970 H\u00f8rsholm, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikte el-Bandak","family":"Lind","sequence":"additional","affiliation":[{"name":"Breye Therapeutics, 2970 H\u00f8rsholm, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8234-1818","authenticated-orcid":true,"given":"Peter","family":"Adamson","sequence":"additional","affiliation":[{"name":"Breye Therapeutics, 2970 H\u00f8rsholm, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3325-240X","authenticated-orcid":true,"given":"Matthew","family":"Campbell","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."},{"name":"FutureNeuro Research Ireland Centre, Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","unstructured":"International Diabetes Federation \u201cFacts & figures\u201d; https:\/\/idf.org\/about-diabetes\/diabetes-facts-figures\/."},{"key":"e_1_3_2_3_2","unstructured":"American Academy of Ophthalmology \u201cDiabetic retinopathy PPP 2024\u201d; https:\/\/aao.org\/education\/preferred-practice-pattern\/diabetic-retinopathy-ppp."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2017-310664"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2021.2809"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/jpm11090885"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oret.2023.10.016"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.25029"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2018.3255"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2013.02.001"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2015.09.004"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.visres.2017.04.003"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10108"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16330"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706631"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2017.06.001"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E14-06-1105"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2017.04.008"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-1519"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0360"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400446200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2015.12.011"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2018.05.003"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-4489"},{"key":"e_1_3_2_25_2","first-page":"2689","article-title":"Connexin 43 (Cx43) upregulation protects retinal endothelial cells against high glucose insult","volume":"54","author":"Barrette K.","year":"2013","unstructured":"K. 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