Muller Alissa, Sullivan Jack, Schwarzer Wibke, Wang Mantian, Park-Windhol Cindy, Hasler Pascal W, Janeschitz-Kriegl Lucas, Duman Mert, Klingler Beryll, Matsell Jane, Hostettler Simon Manuel, Galliker Patricia, Hou Yanyan, Balmer Pierre, Virág Tamás, Barrera Luis Alberto, Young Lauren, Xu Quan, Magda Dániel Péter, Kilin Ferenc, Khadka Arogya, Moreau Pierre-Henri, Fellmann Lyne, Azoulay Thierry, Quinodoz Mathieu, Karademir Duygu, Leppert Juna, Fratzl Alex, Kosche Georg, Sharma Ruchi, Montford Jair, Cattaneo Marco, Croyal Mikaël, Cronin Therese, Picelli Simone, Grison Alice, Cowan Cameron S, Kusnyerik Ákos, Anders Philipp, Renner Magdalena, Nagy Zoltán Zsolt, Szabó Arnold, Bharti Kapil, Rivolta Carlo, Scholl Hendrik P N, Bryson David, Ciaramella Giuseppe, Roska Botond, György Bence
Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
Department of Ophthalmology, University of Basel, Basel, Switzerland.
Nat Med. 2025 Feb;31(2):490-501. doi: 10.1038/s41591-024-03422-8. Epub 2025 Jan 8.
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.
斯塔加特病是一种目前无法治疗的遗传性神经退行性疾病，由于ABCA4基因突变导致功能丧失，进而引发黄斑变性和失明。我们设计了一种双腺相关病毒载体，编码一种分裂内含肽腺嘌呤碱基编辑器，以纠正ABCA4中最常见的突变（c.5882G>A，p.Gly1961Glu）。我们在人类模型中优化了ABCA4碱基编辑，包括视网膜类器官、诱导多能干细胞衍生的视网膜色素上皮（RPE）细胞，以及成人人类视网膜外植体和体外RPE/脉络膜外植体。所得的基因治疗载体在携带突变的小鼠和雌性非人灵长类动物中实现了高水平的基因校正，体内平均编辑率为75%的视锥细胞和87%的RPE细胞，这有可能转化为临床益处。在人类视网膜外植体和RPE/脉络膜外植体中未检测到脱靶编辑。灵长类动物中的高编辑率表明，对于其他可通过碱基编辑靶向治疗的眼部疾病，高效基因编辑具有前景。
