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High-efficiency base editing in the retina in primates and human tissues
Alissa Muller1,2, Jack Sullivan3, Wibke Schwarzer1,2
1Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
Nature Medicine
|January 8, 2025
Summary
This study presents a novel gene therapy for Stargardt disease, utilizing adenine base editing to correct ABCA4 mutations. The therapy shows high efficiency and safety in preclinical models, offering hope for treating this inherited retinal condition.
Area of Science:
- Ophthalmology
- Genetics
- Neurodegenerative Diseases
Background:
- Stargardt disease is an inherited neurodegenerative condition causing macular degeneration and blindness.
- It results from loss-of-function mutations in the ABCA4 gene, and currently lacks effective treatments.
Purpose of the Study:
- To design and optimize a gene therapy approach for correcting the most common ABCA4 mutation.
- To evaluate the efficacy and safety of this gene therapy in relevant preclinical models.
Main Methods:
- Development of a dual adeno-associated viral vector encoding a split-intein adenine base editor.
- Optimization of ABCA4 base editing in human retinal organoids, iPSC-derived RPE cells, and retinal explants.
- In vivo assessment of gene correction efficiency and off-target effects in mutation-carrying mice and nonhuman primates.
Main Results:
- High gene correction rates achieved in vivo: 75% in cones and 87% in RPE cells in nonhuman primates.
- No detectable off-target editing in human retinal and RPE/choroid explants.
- Successful optimization of base editing in various human ocular models.
Conclusions:
- The developed adenine base editor demonstrates significant potential for treating Stargardt disease.
- High in vivo editing efficiency in primates suggests broad applicability for ocular gene therapy.
- This approach offers a promising therapeutic strategy for inherited retinal diseases.
