Post by Toni Cathomen

Base editors are rapidly entering the clinic—but how safe are they? In our latest study, we demonstrate therapeutic correction of familial hemophagocytic lymphohistiocytosis type 3 (FHL3) by base editing of hematopoietic stem cells. Edited stem cells restored cytotoxic immune function and protected the mice from life-threatening hyperinflammation. Beyond the therapeutic proof-of-concept, we systematically compared the editing outcomes of #CRISPR–Cas9 and #CytosineBaseEditing across multiple primary cell types using genome-wide #CASTseq and targeted deep sequencing. Our key findings: 🔹 Base editing effectively restored immune function in vivo. 🔹 #Genotoxicity is strongly platform-, guide-, and cell type-dependent. 🔹 Sequence-level off-target editing does not necessarily predict structural genomic alterations. 🔹 Comprehensive safety assessment should integrate both sequence-level and structural analyses. These findings provide a framework for evaluating the safety of next-generation genome editing technologies as they move toward clinical application. Congratulations to the entire team, in particular lei lei and Masako M. Kaufmann for driving this project, as well as all our collaborators #PeterAichele, Miriam Erlacher, Stephan Ehl, #TatjanaCornu, Melanie Boerries, #JKeithJoung, Anna Illert, and Julian Grünewald whose expertise and collaboration were instrumental in bringing this work to completion! X-PAND, Collaborative Research Center 1597 Small Data, #SFB1160 #CellStemCell #GenomeEditing #CRISPR #BaseEditing #GeneTherapy #StemCells #OffTarget