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@ARTICLE{Raghavan:296127,
      author       = {R. Raghavan and M. J. Friedrich and I. King and S.
                      Chau-Duy-Tam Vo and D. Strebinger and B. Lash and M.
                      Kilian$^*$ and M. Platten$^*$ and R. K. Macrae and Y. Song
                      and L. Nivon and F. Zhang},
      title        = {{R}ational engineering of minimally immunogenic nucleases
                      for gene therapy.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DKFZ-2025-00057},
      pages        = {105},
      year         = {2025},
      abstract     = {Genome editing using CRISPR-Cas systems is a promising
                      avenue for the treatment of genetic diseases. However,
                      cellular and humoral immunogenicity of genome editing tools,
                      which originate from bacteria, complicates their clinical
                      use. Here we report reduced immunogenicity (Red)(i)-variants
                      of two clinically relevant nucleases, SaCas9 and AsCas12a.
                      Through MHC-associated peptide proteomics (MAPPs) analysis,
                      we identify putative immunogenic epitopes on each nuclease.
                      Using computational modeling, we rationally design these
                      proteins to evade the immune response. SaCas9 and AsCas12a
                      Redi variants are substantially less recognized by adaptive
                      immune components, including reduced binding affinity to MHC
                      molecules and attenuated generation of cytotoxic T cell
                      responses, yet maintain wild-type levels of activity and
                      specificity. In vivo editing of PCSK9 with SaCas9.Redi.1 is
                      comparable in efficiency to wild-type SaCas9, but
                      significantly reduces undesired immune responses. This
                      demonstrates the utility of this approach in engineering
                      proteins to evade immune detection.},
      keywords     = {Gene Editing: methods / Humans / CRISPR-Cas Systems /
                      Genetic Therapy: methods / Animals / CRISPR-Associated
                      Protein 9: metabolism / CRISPR-Associated Protein 9:
                      genetics / Protein Engineering: methods / Proprotein
                      Convertase 9: immunology / Proprotein Convertase 9: genetics
                      / Proprotein Convertase 9: metabolism / Mice / HEK293 Cells
                      / T-Lymphocytes, Cytotoxic: immunology / Epitopes:
                      immunology / Endonucleases: metabolism / Endonucleases:
                      genetics / Female / CRISPR-Associated Protein 9 (NLM
                      Chemicals) / Proprotein Convertase 9 (NLM Chemicals) /
                      Epitopes (NLM Chemicals) / Endonucleases (NLM Chemicals) /
                      PCSK9 protein, human (NLM Chemicals)},
      cin          = {D170},
      ddc          = {500},
      cid          = {I:(DE-He78)D170-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39747875},
      pmc          = {pmc:PMC11696374},
      doi          = {10.1038/s41467-024-55522-1},
      url          = {https://inrepo02.dkfz.de/record/296127},
}