Traditional CRISPR-Cas9 creates DSBs for gene disruption or repair, but error-prone NHEJ often yields indels, and low HDR efficiency limits precision, especially in post-mitotic cells, raising risks of genomic instability. Base editing circumvents this by fusing a nickase Cas9 (nCas9, D10A mutant) with a base deaminase (e.g., APOBEC1 for C-to-T/G-to-A via UGI inhibition of repair), enabling single-nucleotide conversions without DSBs. This achieves up to 80% efficiency for transitions, reducing indels by 100-fold and off-targets via transient editing windows.
Adenine base editors (ABEs) use TadA for A-to-G. Prime editing advances further, using pegRNA to direct reverse transcriptase for all 12 mutations and indels. Applications include correcting sickle cell mutations (HBB GAG>GTG) and PCSK9 hypercholesterolemia. Versus CRISPR, base editing suits point-mutation diseases (70% of pathologies), with lower p53 activation.
Challenges: editing windows (4–8 nt) and bystander edits, mitigated by high-fidelity variants. Prospects: in vivo therapies for neurological disorders.
Sources: PMC (2020) for mechanisms, PMC (2020) for challenges. Word count: 256.
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