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38. Jahrestagung der Retinologischen Gesellschaft

Retinologische Gesellschaft
03.-04.07.2026
Badenweiler

Meeting Abstract

Gene editing for macular degeneration

Bence György - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
A. Muller - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
W. Schwarzer - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
M. Wang - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
P.W. Hasler - Department of Ophthalmology, University of Basel, Basel, Switzerland
L. Janeschitz-Kriegl - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland
J. Matsell - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
P.-H. Moreau - SILABE, Université de Strasbourg, Niederhausbergen, France
T Azoulay - Clinique Vétérinaire Agoravet, Strasbourg, France
A. Szabo - Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
B. Roska - Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland; Department of Ophthalmology, University of Basel, Basel, Switzerland

Text

Stargardt 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.