Base Editing: Mechanisms and Therapeutic Applications.

Abstract

Base editing enables the direct, programmable conversion of one nucleotide into another at a defined genomic site without introducing a double-strand break. First reported in 2016, a decade later, it has expanded into a broad family of molecular tools that has now entered clinical trials. This chapter reviews the development of base editing from its origins, including the early transition of cytosine and adenine base editors, to the more recent emergence of transversion editors. For each class, this section describes the mechanism, the optimization of on-target efficiency, product purity, and specificity, as well as the key strengths and limitations. The following discussion focuses on delivery, which remains one of the central bottlenecks for clinical translation, with particular attention to lipid nanoparticles, engineered virus-like particles, and other emerging strategies. Finally, a review of the current clinical landscape is presented. This already includes the first ex vivo multiplex base-edited cell therapy in T-cell leukemia, ex vivo hematopoietic stem cell transplantation targeting hemoglobin disorders, the first systemic in vivo base editing in humans, and, importantly, the first personalized N-of-1 in vivo base-editing therapy, which was developed within a remarkably short time.  These developments show that base editing has moved from a proof-of-concept to a clinically-ready platform with incredible speed, and that the central questions for the field, perhaps, concern the pace at which the surrounding technology, for example delivery, can keep up with base editors themselves.