26rg64 10.3205/26rg64 urn:nbn:de:0183-26rg647 Meeting Abstract György György Bence B

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland

author Muller Muller A. A

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland

author Schwarzer Schwarzer W. W

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland

author Wang Wang M. M

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland

author Hasler Hasler P.W. PW

Department of Ophthalmology, University of Basel, Basel, Switzerland

author Janeschitz-Kriegl Janeschitz-Kriegl L. L

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland Department of Ophthalmology, University of Basel, Basel, Switzerland

author Matsell Matsell J. J

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland

author Moreau Moreau P.-H. PH

SILABE, Université de Strasbourg, Niederhausbergen, France

author Azoulay Azoulay T T

Clinique Vétérinaire Agoravet, Strasbourg, France

author Szabo Szabo A. A

Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary

author Roska Roska B. B

Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland Department of Ophthalmology, University of Basel, Basel, Switzerland

author German Medical Science GMS Publishing House

Düsseldorf

610 20260910 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). M0658 64 Retinologische Gesellschaft 38. Jahrestagung der Retinologischen Gesellschaft Grundlagen-Session Badenweiler 20260703 20260704 26rg64 TextStargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.Gly1961Glu). We optimized ABCA4 base editing in human models, including retinal organoids, induced pluripotent stem cell-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal explants and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in female nonhuman primates, with average editing of 75% of cones and 87% of RPE cells in vivo, which has the potential to translate to a clinical benefit. No off-target editing was detectable in human retinal explants and RPE/choroid explants. The high editing rates in primates show promise for efficient gene editing in other ocular diseases that are targetable by base editing. 0 0 0 0