Ono Pharma Foundation Symposium

Through a combination of protein engineering and protein evolution, we recently developed two classes of base editors (CBE 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 or corrected at target positions in genomic DNA without making double-stranded DNA breaks. The four transition mutations collectively account for most known human pathogenic point mutations. Recently we have expanded the scope of base editing by enhancing its efficiency, product purity, targeting scope, and DNA specificity. By optimizing base editor expression, we developed “max” versions of cytosine and adenine base editors with greatly increase editing efficiency in mammalian cells.  To improve the targeting scope of base editing, we used our phage-assisted continuous evolution (PACE) system to rapidly evolve Cas9 and base editor variants with broadened PAM compatibility, higher DNA specificity, and enhanced editing capabilities. Finally, we are developing new base editor systems that operate on cellular RNA.