A:T TO T:A BASE EDITING THROUGH ADENINE DEAMINATION AND OXIDATION

摘要

The present disclosure provides for base editors which satisfy a need in the art for installation of targeted transversions of thymine (T) to adenine (A), or correspondingly, transversions of adenine (A) to thymine (T). The base editor domains include a nucleic acid programmable DNA binding protein and one or more of an adenosine deaminase or an oxidase domain. The base editors may be engineered through the use of continuous or non-continuous evolution systems, such as phage-assisted continuous evolution (PACE). In particular, the present disclosure provides for adenine-to-thymine (or thymine-to-adenine) base editor variants which satisfy deficiencies of those in art for single-base A:T to T:A transversion mutations. In some embodiments, methods for targeted nucleic acid editing are provided. In some embodiments, pharmaceutical compositions comprising, and vectors and kits for the generation of, targeted base editors are provided. In some embodiments, cells containing such vectors are provided. In some embodiments, methods of treatment comprising administering the base editors are provided.