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WIREs Syst Biol Med
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Immunity to CRISPR Cas9 and Cas12a therapeutics

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Genome‐editing therapeutics are poised to treat human diseases. As we enter clinical trials with the most promising CRISPR‐Cas9 and CRISPR‐Cas12a (Cpf1) modalities, the risks associated with administering these foreign biomolecules into human patients become increasingly salient. Preclinical discovery with CRISPR‐Cas9 and CRISPR‐Cas12a systems and foundational gene therapy studies indicate that the host immune system can mount undesired responses against the administered proteins and nucleic acids, the gene‐edited cells, and the host itself. These host defenses include inflammation via activation of innate immunity, antibody induction in humoral immunity, and cell death by T‐cell‐mediated cytotoxicity. If left unchecked, these immunological reactions can curtail therapeutic benefits and potentially lead to mortality. Ways to assay and reduce the immunogenicity of Cas9 and Cas12a proteins are therefore critical for ensuring patient safety and treatment efficacy, and for bringing us closer to realizing the vision of permanent genetic cures. WIREs Syst Biol Med 2018, 10:e1408. doi: 10.1002/wsbm.1408 This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Translational, Genomic, and Systems Medicine > Translational Medicine Translational, Genomic, and Systems Medicine > Therapeutic Methods
Predicted conformational B‐cell epitopes on Cas9 and Cas12a (Cpf1) proteins. Conformational B‐cell epitopes were predicted by DISCOTOPE 2.0 or ELLIPRO, and the constituent amino acid residues are shaded accordingly. Amino acid residues that are predicted by both algorithms to reside in conformational B‐cell epitopes are indicated (intersect). PDB IDs are indicated for each Cas9 or Cas12a protein, namely SpCas9 (4OO8), SaCas9 (5AXW), CjCas9(5X2G), LbCas12a (5ID6), and AsCas12a (5B43). Amino acid residues that are not predicted to reside in conformational B‐cell epitopes by either algorithms are in white.
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Predicted T‐cell epitopes on Cas9 and Cas12a (Cpf1) proteins. (a) HLA class I‐binding peptide sequences within Cas9 and Cas12a (Cpf1) proteins were predicted with the consensus method hosted on the IEDB 3.0 server using default settings. Twenty‐eight reference HLA class I allotypes (rows) were used for the prediction along the entire length of the Cas9 or Cas12a proteins, and the predicted propensities of peptide binding to each HLA class I allotype are denoted in red (column). Lower percentile ranks, as depicted with darker shades of red, denote peptides predicted to be more immunogenic. Black bars at the bottom of each panel depict residue positions of peptide sequences that are predicted to bind more than half of the reference HLA class I allotypes. (b) HLA class II‐binding peptide sequences within Cas9 and Cas12a proteins were predicted with the consensus method hosted on the IEDB 3.0 server using default settings. Twenty‐seven reference HLA class II allotypes (rows) were used for the prediction.
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Immunological risks from CRISPR‐Cas9 and CRISPR‐Cas12a (Cpf1) therapeutics. Genome‐editing therapeutics introduce foreign nucleic acids and proteins into the circulation and cells, which can activate the innate, cellular, and humoral immunity in human patients. The key obstacle in translating CRISPR therapeutics to the clinic is hence to identify, diminish, and monitor these immunological risks before adverse immune reactions.
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Reducing risks of immune reactions toward CRISPR Cas9 and Cas12a (Cpf1). The immunoglobulin/B‐cell receptor (BCR) and HLA genes are the most polymorphic loci in the human genome; understanding how each BCR allele could bind the Cas9 and Cas12a proteins and what immunopeptides each HLA allele presents could bring us closer to in silico prediction of immunogenic predisposition. Understanding the innate immune machinery that detects and responds to CRISPR‐Cas9 and Cas12a therapeutics would guide vector choice and engineering efforts. Identification of antigenic regions on CRISPR‐Cas9 and Cas12a would enable deimmunization and epitope masking by directed evolution or rational design. Delivery vectors and administration routes that allow tissue‐specific expression could confine possible antigenic exposure to the target site. Immunosuppression by pharmacological immunosuppressants and/or regulatory T‐cells (Tregs) could reduce undesired immune reactivity.
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