Genotoxicity profiling reveals distinct platform- and cell type–specific effects in therapeutic gene editing for genetic hyperinflammation

Here, we applied cytosine base editing (CBE) to disrupt a cryptic splice-site mutation in the Unc13d locus of Jinx mice, a model of familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Efficient editing (62–89%) in fibroblasts, T cells, and hematopoietic stem cells (HSCs) restored Unc13d splicing, reconstituted cytotoxic T cell function, and protected mice from virus-triggered hyperinflammation after transplantation of edited HSCs.

Comparative genotoxicity profiling revealed distinct platform- and cell type–specific patterns: hyperactive CBE induced broader off-target activity and more structural variants than CRISPR–Cas9. While off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish therapeutic base editing for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide clinical translation of genome editors.