Highly efficient biallelic correction of homozygous COL7A1 mutation using ABE8e adenine base editor.

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin disorder characterized by severe skin blistering. With no cure at present, we have pursued a gene repair approach using base editing of COL7A1. Following on from our previous report of highly efficient base editing using the novel base editor, ABE8e, here we explore the use of lipid nanoparticle (LNP)-based delivery systems instead of electroporation to effect base editing in RDEB fibroblasts and correct a missense G > A mutation. We demonstrate increasingly high editing efficiencies, averaging 90%, which vary with the ABE8e dosage. We then demonstrate the viability of topical delivery of mRNA encapsulated in an LNP. Our work underscores the translational potential of this therapeutic route for DEB.