Journal Article

DKFZ-2026-01155

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genotoxicity profiling reveals distinct platform-and cell type-specific effects in therapeutic gene editing for genetic hyperinflammation.

Lei, L. ; Kaufmann, M. M. ; Lao, J. ; Thoulass, G. ; Ammann, S. ; Xiao, H. ; Rhiel, M. ; Dettmer-Monaco, V. ; Grünewald, J. ; Andrieux, G.DKFZ* ; Alzubi, J. ; Miller, B. R. ; Weißert, K. ; Gräßel, L.DKFZ* ; Schell, C. ; Illert, A. L.DKFZ* ; Joung, J. K. ; Börries, M.DKFZ* ; Cornu, T. I. ; Ehl, S. ; Erlacher, M. ; Aichele, P. ; Cathomen, T.DKFZ*

2026
Elsevier Amsterdam [u.a.]

Abstract: Base editors enable precise correction of point mutations without requiring DNA double-strand breaks, yet platform- and cell type-specific genotoxicities remain incompletely characterized. 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. Although off-target sequence edits persisted, the stability of CBE-induced chromosomal translocations differed between cell types. These findings establish base editing as a therapeutic strategy for a genetically predisposed hyperinflammatory syndrome and underscore the importance of context-specific safety profiling to guide the clinical translation of genome editors.

Keyword(s): CAST-seq ; CRISPR-Cas ; FHL type 3 ; base editing ; cytosine base editor ; cytotoxicity ; genotoxicity ; hematopoietic stem cell transplantation ; hyperinflammation ; off-target effects

Note: #DKTKZFB9# / epub

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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