Base Editing: A Strong Contender in Cell and Gene Therapy
Base editors, DNA double-strand break (DSB)-independent genome modification agents, have been recognized alongside prime editors as key technologies to watch this year,1 and advances to date have been encouraging.
The fields of cell and gene therapy and genome editing increasingly overlap, and results from published clinical trials that include CRISPR-based therapies show early evidence of feasibility and efficacy in humans. Advanced gene therapies not only show potential for curing rare, debilitating monogenic diseases, but they also offer hope for treating complex disorders, including cardiovascular disorders.
Many of the deleterious, unintended off-target effects of CRISPR-Cas gene editing are underpinned by the system’s reliance on DSBs to edit target genes. Nuclease-induced formation of insertions and deletions (indels) at a guide RNA (gRNA)-specific target locus allows for genetic disruption and consequent functional protein knockout. This can provide an effective therapeutic strategy for some monogenic disorders.8 Legitimate strategies to overcome gRNA-dependent off-target editing include rational gRNA design, the use of high-fidelity nuclease orthologues, the exercise of temporal control over editing activity, and the prevention of repeated nuclease cleavage.9
The capacity to induce a single-base conversion can be harnessed to correct a pathogenic point mutation, silence a disease-causing gene, skip a disease-causing exon, activate a specific gene, or fine-tune engineered immune cell therapies, providing multiple strategies to address a wide range of diseases.
Although the deleterious outcomes of triggering DSBs are mitigated using base editing, researchers continue to “pressure test” the system to comprehensively understand the mechanisms of action and evaluate the safety profile of this next-generation gene editing tool to ensure a smooth transition to the clinic. Base editing offers a distinct advantage over its predecessors: It facilitates precise, viable, multigene editing in a wide range of therapeutically relevant cell types. The rapid progress and promising outcomes to date make base editing a strong contender in the development of innovative cell and gene therapies.
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