Building A Differentiated Portfolio Of Base Editors For Therapeutic Applications

By Lucas F. Ribeiro, Principal Scientist, Technology

A comprehensive engineering framework is used to generate adenine base editors (ABEs) with finely tuned functional properties suitable for a wide range of therapeutic targets. The platform integrates evolutionarily diverse nucleases with broad PAM compatibility and modular protein architectures, enabling precise positioning of target adenines and improved editing efficiency. Inlaid architecture optimization paired with deaminase‑directed evolution produces ABEs with distinct profiles—ranging from high‑potency, broad‑window editors to precision‑tuned variants with narrow windows and context‑selective behavior.

High‑throughput screening in E. coli identifies top‑performing inlaid constructs, such as C92, which are further refined through iterative deaminase evolution. Lentiviral characterization across hundreds of clinically relevant variants reveals reproducible functional classes defined by differences in overall activity, editing‑window geometry, context preference, and unexpected CBE/INDEL/off‑target behaviors.

The resulting portfolio of ABEs expands target accessibility, improves alignment of editing windows, reduces unintended edits, and supports the development of precise and effective therapeutic genome‑editing strategies.