Analysis of CRB1 Pathogenic Variants Correctable with CRISPR Base and Prime Editing

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• The retina has three Crumbs homologue-1 (CRB1) isoforms with cell-specific expression.
• CRB1 mutations cause retinal degenerations, and gene augmentation strategies face challenges.
• Gene editing presents a potential alternative for treating CRB1-associated retinal diseases.

Purpose of the Study:

• To analyze the prevalence and spectrum of CRB1 pathogenic variants.
• To determine the amenability of these variants to base and prime editing.

Main Methods:

• Analysis of the Leiden Open Variation Database for CRB1 variants.
• Assessment of variant types suitable for base and prime editing techniques.

Main Results:

• 54.5% of CRB1 pathogenic variants are amenable to base editing.
• 99.8% of CRB1 pathogenic variants are amenable to prime editing.
• The c.2843G>A, p.(Cys948Tyr) variant is the most common editable CRB1 mutation.

Conclusions:

• Base and prime editing are highly efficient for correcting CRB1 pathogenic variants.
• Gene editing therapeutics offer a viable alternative to gene augmentation for CRB1 retinal degenerations.