Protein engineering technologies for development of next-generation genome editors

Base editors and prime editors have emerged as promising tools for the modeling and treatment of genetic diseases due to their ability to introduce targeted modifications in the genomic DNA of living cells. Several engineering approaches have been applied to improve their performance, ranging from simple protein design approaches to complex directed evolution schemes that can probe a vast landscape of mutational variants with minimal user intervention. These extensive efforts have led to new generations of editors with enhanced properties such as increased editing activity, tailored editing windows, increased targetability, smaller construct size for viral delivery, and decreased off-target effects. In this manuscript we review protein engineering technologies that have been recently utilized to create an ever-evolving landscape of high-performance gene editing tools specifically designed for genetic targets of interest and that have redefined what is possible in the field of precision medicine.