Point mutations represent the majority of known human genetic variants associated with disease but are difficult to correct cleanly and efficiently using standard genome editing methods. In this lecture I will describe the development, application, and evolution of base editing, a novel approach to genome editing that directly converts a target base pair to another base pair in living cells without requiring DNA backbone cleavage or donor DNA templates. Through a combination of protein engineering and protein evolution, we recently developed two classes of base editors (BE4 and ABE) that together enable all four types of transition mutations (C to T, T to C, A to G, and G to A) to be efficiently and cleanly installed at target positions in genomic DNA. The four transition mutations collectively account for most known human pathogenic point mutations. Base editing has been successfully performed in a wide range of organisms including bacteria, fungi, plants, fish, frogs, mammals, and even human embryos. We have characterized and substantially improved key molecular features of both classes of base editors, including their efficiency, product purity, targeting scope, and DNA specificity. We also show that base editing can function in vivo in post-mitotic cells that do not support efficient homology-directed repair. Base editing can be used to correct pathogenic point mutations, introduce disease-suppressing mutations, and create cell and animal models of human disease.<br/>

Base editing: Chemistry on a target nucleotide in the genome of living cells

256th National Meeting (2018)

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