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| 001 | 278643 | ||
| 005 | 20240312125751.0 | ||
| 024 | 7 | _ | |a 10.1016/j.jaci.2023.08.003 |2 doi |
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| 024 | 7 | _ | |a 0091-6749 |2 ISSN |
| 024 | 7 | _ | |a 1085-8725 |2 ISSN |
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| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Dettmer-Monaco, Viviane |b 0 |
| 245 | _ | _ | |a Gene editing of hematopoietic stem cells restores T cell response in familial hemophagocytic lymphohistiocytosis. |
| 260 | _ | _ | |a Amsterdam [u.a.] |c 2024 |b Elsevier |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1710244647_32556 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a 2024 Jan;153(1):243-255.e14 |
| 520 | _ | _ | |a 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. |
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| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de |
| 650 | _ | 7 | |a CAST-Seq |2 Other |
| 650 | _ | 7 | |a CRISPR-Cas |2 Other |
| 650 | _ | 7 | |a T cell repertoire |2 Other |
| 650 | _ | 7 | |a autologous stem cell transplantation |2 Other |
| 650 | _ | 7 | |a gene therapy |2 Other |
| 650 | _ | 7 | |a genome editing |2 Other |
| 650 | _ | 7 | |a genotoxicity |2 Other |
| 650 | _ | 7 | |a hemophagocytic lymphohistiocytosis |2 Other |
| 650 | _ | 7 | |a hyperinflammation |2 Other |
| 700 | 1 | _ | |a Weißert, Kristoffer |b 1 |
| 700 | 1 | _ | |a Ammann, Sandra |b 2 |
| 700 | 1 | _ | |a Monaco, Gianni |b 3 |
| 700 | 1 | _ | |a Lei, Lei |b 4 |
| 700 | 1 | _ | |a Gräßel, Linda |0 P:(DE-HGF)0 |b 5 |
| 700 | 1 | _ | |a Rhiel, Manuel |b 6 |
| 700 | 1 | _ | |a Rositzka, Julia |b 7 |
| 700 | 1 | _ | |a Kaufmann, Masako M |b 8 |
| 700 | 1 | _ | |a Geiger, Kerstin |b 9 |
| 700 | 1 | _ | |a Andrieux, Geoffroy |b 10 |
| 700 | 1 | _ | |a Lao, Jessica |b 11 |
| 700 | 1 | _ | |a Thoulass, Gudrun |b 12 |
| 700 | 1 | _ | |a Schell, Christoph |b 13 |
| 700 | 1 | _ | |a Börries, Melanie |0 P:(DE-He78)49bdb7cb4094fbf35c269ffa3e93ebc6 |b 14 |u dkfz |
| 700 | 1 | _ | |a Illert, Anna Lena |0 P:(DE-HGF)0 |b 15 |
| 700 | 1 | _ | |a Cornu, Tatjana I |b 16 |
| 700 | 1 | _ | |a Ehl, Stephan |b 17 |
| 700 | 1 | _ | |a Aichele, Peter |b 18 |
| 700 | 1 | _ | |a Cathomen, Toni |b 19 |
| 773 | _ | _ | |a 10.1016/j.jaci.2023.08.003 |g p. S0091674923009892 |0 PERI:(DE-600)2006613-2 |n 1 |p 243-255.e14 |t The journal of allergy and clinical immunology |v 153 |y 2024 |x 0091-6749 |
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