Molecular therapy. Nucleic acidsJan 2, 2023

Restoring vision in mice with inherited blindness using gene-editing therapy

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 9, 2026

Abstract

Subretinal injection of AAV-ABE in mice resulted in an A to G transition in the RPE65 gene.

Leber congenital amaurosis (LCA) is linked to specific pathogenic variants in genes related to retinal function.
Base editing tools can correct genetic mutations without causing DNA double-stranded breaks.
In an animal model of LCA with a specific nonsense mutation, successful editing led to the recovery of wild-type mRNA and RPE65 protein.
Light-induced electrical responses in the retina improved following subretinal injection of AAV-ABE.
ABEs may provide a more effective method for correcting pathogenic variants in LCA compared to previous editing strategies.

Simplified

Leber congenital amaurosis (LCA), an inherited retinal degeneration, causes severe visual dysfunction in children and adolescents. In patients with LCA, pathogenic variants, such as, are evident in specific genes, related to the functions of retinal pigment epithelium and photoreceptors. In contrast to the original Cas9, base editing tools can correct pathogenic substitutions without generation of DNA double-stranded breaks (DSBs). In this study, dual adeno-associated virus (AAV) vectors containing split adenine base editors (ABEs) with-splicing intein were prepared forbase editing in retinal degeneration of 12 () mice, an animal model of LCA, possessing a nonsense mutation of C to T transition in thegene (p.R44X). Subretinal injection of AAV-ABE in retinal pigment epithelial cells ofmice resulted in an A to G transition. The on-target editing was sufficient for recovery of wild-type mRNA, RPE65 protein, and light-induced electrical responses from the retina. Compared with our previous therapeutic editing strategies using Cas9 and prime editing, or with the gene transfer strategy shown in the current study, our results suggest that, considering the editing efficacy and functional recovery, ABEs could be a strong, reliable method for correction of pathogenic variants in the treatment of LCA. RPE65trans in vivo rd12Rpe65rd12

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Restoring vision in mice with inherited blindness using gene-editing therapy

Abstract

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