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Current standard treatment, anti\u2010vascular endothelial growth factor (VEGF) therapy, while effective, can be associated with severe local and systemic side effects and resistance in some patients, necessitating novel therapeutic approaches. Evidence from wet age\u2010related macular degeneration (AMD) donor eyes and patients suggests that functional, quiescent CNV can aid photoreceptor survival. Therefore, stabilizing functional neovessels rather than removing them could offer an effective alternative for treating pathological CNV. Pigment epithelium\u2010derived factor (PEDF), a multifunctional protein with antiangiogenic, neuroprotective, and vessel\u2010stabilizing properties, is a promising candidate for this approach. The efficacy of intravitreally injected PEDF protein, alone or in combination with bevacizumab, was investigated and compared to bevacizumab monotherapy in a VEGF overexpression\u2010induced CNV rat model using in\u00a0vivo imaging and histology. Following PEDF\u2009+\u2009bevacizumab treatment, a significant reduction in CNV thickness was observed, comparable to bevacizumab monotherapy. Notably, only PEDF and PEDF\u2009+\u2009bevacizumab treatments significantly preserved retinal thickness and enhanced photoreceptor survival at the CNV site. Ultrastructural analysis revealed that PEDF and PEDF\u2009+\u2009bevacizumab treatments increased CNV vessel lumina, stabilized these vessels by reducing the thickness of the extracellular matrix and refining its structure, and enhanced vessel fenestration and pericyte coverage, making PEDF\u2010based therapy more effective than bevacizumab monotherapy. These findings suggest that supporting the maintenance of functional CNV vessels using PEDF may represent a novel and innovative strategy for the treatment of wet AMD.<\/jats:p>","DOI":"10.1096\/fj.202501704rr","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T14:46:23Z","timestamp":1760021183000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pigment Epithelium\u2010Derived Factor (PEDF)\u2010Based Therapy Induced Photoreceptor Survival by Stabilizing Choroidal Neovessels in a VEGF Overexpression CNV Rat Model"],"prefix":"10.1096","volume":"39","author":[{"given":"Alexander V.","family":"Tschulakow","sequence":"first","affiliation":[{"name":"Centre for Ophthalmology, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"},{"name":"Institute for Ophthalmic Research, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"},{"name":"OcuTox GmbH, Preclinical Drug Assessment  Hechingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Xi","sequence":"additional","affiliation":[{"name":"Centre for Ophthalmology, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Schraermeyer","sequence":"additional","affiliation":[{"name":"Centre for Ophthalmology, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"},{"name":"Institute for Ophthalmic Research, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"},{"name":"OcuTox GmbH, Preclinical Drug Assessment  Hechingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2322-511X","authenticated-orcid":false,"given":"Sylvie","family":"Julien","sequence":"additional","affiliation":[{"name":"Centre for Ophthalmology, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"},{"name":"Institute for Ophthalmic Research, University Medical Center Eberhard Karls University of Tuebingen  T\u00fcbingen Germany"},{"name":"OcuTox GmbH, Preclinical Drug Assessment  Hechingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-014-2733-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2012.04.005"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-40406-y"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2017.04.028"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.05.003"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.17-23747"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2014-305149"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11596-020-2253-6"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-010-1315-z"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100921"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218242"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.64.5.28"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.26074"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00265-2"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-015-2993-3"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2016.208"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.4274\/tjo.27448"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.17116\/oftalma2018134051289"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-009-0082-x"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1167\/tvst.7.5.19"},{"key":"e_1_2_10_22_1","first-page":"1186","article-title":"Choroidal Neovascularization Can Help Photoreceptors to Survive in Late AMD","volume":"55","author":"Biesemeier A. 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