Enhanced HDR-mediated correction of heterozygous mutations for recessive dystrophic epidermolysis bullosa.

Gene editing facilitated by homology-directed repair (HDR) holds great potential for treating monogenetic disorders such as recessive dystrophic epidermolysis bullosa (RDEB). However, low efficiency and variability between loci must be overcome for its widespread adoption into personalized therapies. To address these challenges, we developed a highly efficient and versatile gene editing strategy for RDEB that incorporates the small molecule inhibitor M3814 to enhance HDR.

Efficient Dual Cas9 Nickase Correction of a Prevalent Pathogenic Variant for Junctional Epidermolysis Bullosa.

Gene editing facilitated by homology-directed repair represents a promising strategy for precisely correcting pathogenic variants underlying monogenic disorders, including the life-threatening skin blistering condition junctional epidermolysis bullosa (JEB). Frequent reports of unintended off-target genotoxicity associated with conventional Cas9 nuclease editing have increasingly led to the adoption of dual-Cas9 nickases (dual-Cas9n) owing to their improved safety profile. However, rates of precise repair obtained with such strategies remain low.