Small-molecule enhancers of CRISPR-induced homology-directed repair in gene therapy: A medicinal chemist's perspective

Abstract

CRISPR technologies are increasingly being investigated and utilized for the treatment of human genetic diseases via genome editing. CRISPR-Cas9 first generates a targeted DNA double-stranded break, and a functional gene can then be introduced to replace the defective copy in a precise manner by templated repair via the homology-directed repair (HDR) pathway. However, this is challenging owing to the relatively low efficiency of the HDR pathway compared with a rival random repair pathway known as non-homologous end joining (NHEJ). Small molecules can be employed to increase the efficiency of HDR and decrease that of NHEJ to improve the efficiency of precise knock-in genome editing. This review discusses the potential usage of such small molecules in the context of gene therapy and their drug-likeness, from a medicinal chemist's perspective.

Keywords: CRISPR; DNA repair; Gene therapy; Genome editing; Homology-directed repair; Small molecules.