Home > Publications database > Rational engineering of minimally immunogenic nucleases for gene therapy. > print

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005     20250112014717.0
024 7 _ |a 10.1038/s41467-024-55522-1
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041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Raghavan, Rumya
|b 0
245 _ _ |a Rational engineering of minimally immunogenic nucleases for gene therapy.
260 _ _ |a [London]
|c 2025
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 7 |a CRISPR-Associated Protein 9
|0 EC 3.1.-
|2 NLM Chemicals
650 _ 7 |a Proprotein Convertase 9
|0 EC 3.4.21.-
|2 NLM Chemicals
650 _ 7 |a Epitopes
|2 NLM Chemicals
650 _ 7 |a Endonucleases
|0 EC 3.1.-
|2 NLM Chemicals
650 _ 7 |a PCSK9 protein, human
|0 EC 3.4.21.-
|2 NLM Chemicals
650 _ 2 |a Gene Editing: methods
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a CRISPR-Cas Systems
|2 MeSH
650 _ 2 |a Genetic Therapy: methods
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a CRISPR-Associated Protein 9: metabolism
|2 MeSH
650 _ 2 |a CRISPR-Associated Protein 9: genetics
|2 MeSH
650 _ 2 |a Protein Engineering: methods
|2 MeSH
650 _ 2 |a Proprotein Convertase 9: immunology
|2 MeSH
650 _ 2 |a Proprotein Convertase 9: genetics
|2 MeSH
650 _ 2 |a Proprotein Convertase 9: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a T-Lymphocytes, Cytotoxic: immunology
|2 MeSH
650 _ 2 |a Epitopes: immunology
|2 MeSH
650 _ 2 |a Endonucleases: metabolism
|2 MeSH
650 _ 2 |a Endonucleases: genetics
|2 MeSH
650 _ 2 |a Female
|2 MeSH
700 1 _ |a Friedrich, Mirco J
|b 1
700 1 _ |a King, Indigo
|0 0009-0003-3048-4763
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700 1 _ |a Chau-Duy-Tam Vo, Samuel
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700 1 _ |a Strebinger, Daniel
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700 1 _ |a Lash, Blake
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700 1 _ |a Kilian, Michael
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700 1 _ |a Platten, Michael
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700 1 _ |a Macrae, Rhiannon K
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700 1 _ |a Song, Yifan
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700 1 _ |a Nivon, Lucas
|b 10
700 1 _ |a Zhang, Feng
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773 _ _ |a 10.1038/s41467-024-55522-1
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