Leung, Amy;
Perdigao, Pedro RL;
Sacristan-Reviriego, Almudena;
Sladen, Paul E;
Aguzzi, Erika A;
Rezek, Farah O;
Ziaka, Kalliopi;
... Van der Spuy, Jacqueline; + view all
(2025)
Adenine base editor correction of pathogenic variations associated with inherited retinal dystrophy in patient iPSC and retinal organoids.
Molecular Therapy Nucleic Acids
, 36
(4)
, Article 102777. 10.1016/j.omtn.2025.102777.
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Abstract
Inherited retinal dystrophies (IRDs) are a group of incurable, genetically heterogeneous diseases that cause progressive degeneration of the retina, leading to the loss of vision. Genome editing technologies offer a powerful prospect for mutation correction and single-dose cures for these diseases. Here, we investigated the potential of adenine base editing (ABE) to correct a panel of causative genetic variations in patient-derived induced pluripotent stem cells (iPSCs) and identified parameters that can efficiently correct a pathogenic variation in the AIPL1 gene (c.665G>A, p.Trp222∗), which is associated with autosomal recessive Leber congenital amaurosis type 4. To investigate correction of the variant in a patient-relevant model, retinal organoids (ROs) were derived from corrected isogenic and patient-derived iPSCs. Adenine base editor components were delivered to ROs via lipofection as chemically modified RNA or via a split intein system following dual-AAV transduction. The data show AIPL1 rescue in photoreceptor cells with both delivery systems and restoration of the AIPL1 target protein, cyclic guanosine monophosphate phosphodiesterase 6—a critical component of the visual transduction system—in treated rod photoreceptors. These proof-of-principle experiments highlight the utility of ROs for investigating the potential of ABE technology as a means to treat IRDs.
| Type: | Article |
|---|---|
| Title: | Adenine base editor correction of pathogenic variations associated with inherited retinal dystrophy in patient iPSC and retinal organoids |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.omtn.2025.102777 |
| Publisher version: | https://doi.org/10.1016/j.omtn.2025.102777 |
| Language: | English |
| Additional information: | Copyright © 2025 The Authors. Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | MT: RNA/DNA editing; inherited retinal dystrophy; CRISPR; Cas9; base editing; retinal organoid; induced pluripotent stem cell; Leber congenital amaurosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10219648 |
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