Base editor ABE8e achieves high-efficiency PCSK9 edits while supporting human embryo development

In a new study, scientists applied the adenine base editor ABE8e-V106W in protein form to human embryos at the moment of fertilization, targeting the PCSK9 and HBG loci. The approach succeeded in editing every PCSK9 allele, enabling embryos to develop to the blastocyst stage and to generate homozygous edited stem-cell lines without any detectable insertions or deletions. Nonetheless, a small number of embryos exhibited on-target chromosome breakage and other chromosomal abnormalities, and off-target as well as by-stander edits were observed in a mosaic distribution.

Supplying the editor as mRNA led to frequent embryo arrest, likely caused by guide-independent deaminase activity. Compared with traditional Cas9-mediated double-strand breaks, base-editor induced lesions were repaired more efficiently, yet the occurrence of genomic instability and mosaicism currently limits clinical application in human reproduction. The authors provide extensive sequencing data and analysis code to support further evaluation of base-editing safety.