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| Home > Publications database > Gene editing of hematopoietic stem cells restores T cell response in familial hemophagocytic lymphohistiocytosis. |
| Home > Publications database > Gene editing of hematopoietic stem cells restores T cell response in familial hemophagocytic lymphohistiocytosis. |
| Journal Article | DKFZ-2023-01687 |
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2024
Elsevier
Amsterdam [u.a.]
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Please use a persistent id in citations: doi:10.1016/j.jaci.2023.08.003
Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for ∼30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene, which result in impaired degranulation of cytotoxic vesicles and hence compromised T and NK cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show high mortality.We sought to develop and evaluate a curative genome editing strategy in the preclinical FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site (cSD) in Unc13d intron 26 and develop clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV).We employed CRISPR-Cas technology to delete the disease-underlying mutation in HSCs, and transplanted Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Safety studies included extensive genotyping and CAST-Seq based off-target analyses. Cure from HLH predisposition was assessed by LCMV infection.Hematopoietic cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wildtype cells were comparable. While LCMV challenge resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH.Our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T cell response in the absence of genotoxicity-associated clonal outgrowth.
Keyword(s): CAST-Seq ; CRISPR-Cas ; T cell repertoire ; autologous stem cell transplantation ; gene therapy ; genome editing ; genotoxicity ; hemophagocytic lymphohistiocytosis ; hyperinflammation
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