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The precision strategy of human genome correction via a set of circular donor DNA and its cleaver
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DOI：10.3389/fgeed.2026.1718252.png)
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Abstract
En 中文
Homologous recombination (HR) corrects a mutational sequence causing a genetic disease by replacing it with the normal sequence to restore a healthy state in humans. A targeted genomic breakage; such as that induced by CRISPR–Cas9; can trigger a copy-paste-type HR event; however; CRISPR–Cas9 more frequently induces imprecise non-homologous end-joining events; leading to one-step multiple knockout products for paralogous genes or homologous alleles; which can be considered a unique advantage. We have established a precision strategy for crossover-type HR-based gene editing; primed by intra-cellular circular donor cleavage (InCDC). The InCDC technique generates targeted duplication of the circular donor plasmid at the target locus in human cells; forming a doublet configuration comprising the donor DNA with the designed sequence and the target DNA with the original sequence; with much higher efficiency than conventional donor linearization techniques. This doublet form leads to the singlet form; resulting in retention of the designed allele. We found that the safety distance within the designed circular donor plasmid and its intra-cellular cleavage was particularly critical to protect a designed sequence from enzymatic exclusion; and we propose that InCDC technology enables precision genome editing; such as the replacement of a genetic disease-causing allele with the correctly designed allele.
Keywords:
crossover-type homologous recombination
intra-cellular circular donor cleavage
natural replacement
safety distance
targeted duplication
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