ABSTRACT
Ex vivo gene editing in hematopoietic stem and progenitor cells (HSPCs) represents a promising curative treatment strategy for monogenic blood disorders. Gene editing using the homology-directed repair (HDR) pathway enables precise genetic modifications ranging from single base pair correction to replacement or insertion of large DNA segments. Hence, HDR-based gene editing could facilitate broad application of gene editing across monogenic disorders, but the technology still faces challenges for clinical translation. Among these, recent studies demonstrate induction of a DNA damage response (DDR) and p53 activation caused by DNA double-strand breaks and exposure to recombinant adeno-associated virus vector repair templates, resulting in reduced proliferation, engraftment, and clonogenic capacity of edited HSPCs. While different mitigation strategies can reduce this DDR, more research is needed on this phenomenon to ensure safe and efficient implementation of HDR-based gene editing in the clinic.
