Authors
Kalmodia, S., Aparicio, J. G., Stepanian, K., Beck, A., Salas, A., Harutyunyan, N., Galvan, P., Bai, J., Hayun, M., Li, M., Fernandez, G. E., Reid, M. W., Schmidt, R. J., Argyriou, C., Cobrinik, D., Nagiel, A.
Abstract
Autosomal dominant Best vitelliform macular dystrophy (BVMD) caused by variants in BEST1 is characterized by dysfunction of the macular retinal pigment epithelium (RPE) and secondary degeneration of the photoreceptors. There are currently no approved treatments for BVMD condition, which may be due in part to concerns with whether it can be adequately treated by gene augmentation. Here, we evaluated whether the dominant pathogenic BEST1 allele can be corrected by base editing. We identified a patient with a likely pathogenic BEST1 c.851A>G(p. Tyr284Cys) variant that was amenable to cytidine base editing. After establishing patient-derived induced pluripotent stem cells (iPSCs), we corrected the pathogenic variant in the iPSCs to obtain corrected iPSCs with the same genetic background. We then used a dual adeno-associated virus (AAV) split-intein system to deliver a CRISPR-associated protein 9 cytidine base editor (SpCas9-CBE) to BEST1 c.851A>G mutant RPE monolayers and achieved editing of the pathogenic allele with a maximum efficiency of 13.42 +/- 3.64% (mean +/- SD). Corrected iPSC-derived RPE normalized the appearance of the monolayer, improved barrier integrity, reduced cell death, and restored the RPE specific transcriptome. Together, these results demonstrate progress towards allele-specific base editing in dominantly inherited retinal disorders.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 16 Jul 2026.
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