% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{DettmerMonaco:278643,
      author       = {V. Dettmer-Monaco and K. Weißert and S. Ammann and G.
                      Monaco and L. Lei and L. Gräßel$^*$ and M. Rhiel and J.
                      Rositzka and M. M. Kaufmann and K. Geiger and G. Andrieux
                      and J. Lao and G. Thoulass and C. Schell and M. Börries$^*$
                      and A. L. Illert$^*$ and T. I. Cornu and S. Ehl and P.
                      Aichele and T. Cathomen},
      title        = {{G}ene editing of hematopoietic stem cells restores {T}
                      cell response in familial hemophagocytic
                      lymphohistiocytosis.},
      journal      = {The journal of allergy and clinical immunology},
      volume       = {153},
      number       = {1},
      issn         = {0091-6749},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-01687},
      pages        = {243-255.e14},
      year         = {2024},
      note         = {2024 Jan;153(1):243-255.e14},
      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.},
      keywords     = {CAST-Seq (Other) / CRISPR-Cas (Other) / T cell repertoire
                      (Other) / autologous stem cell transplantation (Other) /
                      gene therapy (Other) / genome editing (Other) / genotoxicity
                      (Other) / hemophagocytic lymphohistiocytosis (Other) /
                      hyperinflammation (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37595758},
      doi          = {10.1016/j.jaci.2023.08.003},
      url          = {https://inrepo02.dkfz.de/record/278643},
}