{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T11:23:06Z","timestamp":1772104986992,"version":"3.50.1"},"reference-count":128,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Age-related macular degeneration (A\u039cD) remains a leading cause of irreversible vision loss. \u0399n neovascular A\u039cD (nA\u039cD), frequent intravitreal anti-V\u0395GF injections create substantial treatment burden, while approved therapies for geographic atrophy (GA) provide modest slowing of progression. Ocular gene therapy aims to achieve sustained intraocular expression of therapeutic proteins after a single administration. \u03a4his review summarises the biological rationale, vector platforms, and delivery routes relevant to A\u039cD, with emphasis on adeno-associated virus (AAV) systems, capsid engineering, and compartment-specific administration (intravitreal, subretinal, and suprachoroidal). We synthesise the clinical landscape for sustained anti-V\u0395GF expression approaches in nA\u039cD and complement-modulating strategies for GA, and highlight how trials increasingly prioritise injection-burden reduction, anatomical endpoints, and biomarkers of target engagement. \u039aey challenges include intraocular inflammation and neutralising antibodies (particularly with intravitreal dosing), variability and durability of transgene expression, surgical risks associated with subretinal delivery, and practical constraints related to manufacturing scale, cost, and long-term safety surveillance for non-removable therapies. Overall, gene therapy offers a plausible route towards durable, mechanism-targeted A\u039cD management, but its clinical role will depend on robust controlled trials and multi-year follow-up.<\/jats:p>","DOI":"10.3390\/cells15040376","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T10:00:52Z","timestamp":1771840852000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gene Therapy Advancements in Age-Related Macular Degeneration Treatment"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7071-1557","authenticated-orcid":false,"given":"Efstratia","family":"Amaxilati","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4283-5260","authenticated-orcid":false,"given":"Eleftherios","family":"Chatzimichail","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Basel, 4056 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2441-545X","authenticated-orcid":false,"given":"Georgios N.","family":"Tsiropoulos","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Motta","sequence":"additional","affiliation":[{"name":"Eye Unit, Department of Neuroscience, University of Padua, 35131 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1545-6199","authenticated-orcid":false,"given":"Theo","family":"Empeslidis","sequence":"additional","affiliation":[{"name":"Vantage Biosciences, London SW1Y 5ES, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zisis","family":"Gatzioufas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Basel, 4056 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8399-7456","authenticated-orcid":false,"given":"Georgios D.","family":"Panos","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"},{"name":"Division of Ophthalmology and Visual Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S0140-6736(22)02609-5","article-title":"Age-related macular degeneration","volume":"401","author":"Guymer","year":"2023","journal-title":"Lancet"},{"key":"ref_2","first-page":"e29583","article-title":"Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment","volume":"14","author":"Vyawahare","year":"2022","journal-title":"Cureus"},{"key":"ref_3","first-page":"e74911","article-title":"Maculopathies: A Systematic Literature Review on Pathophysiology, Public Health, and Treatment","volume":"16","author":"Pantelidou","year":"2024","journal-title":"Cureus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41572-021-00265-2","article-title":"Age-related macular degeneration","volume":"7","author":"Fleckenstein","year":"2021","journal-title":"Nat. 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