{"doi":"10.1016/j.ymthe.2020.05.007","title":"Immunity to Cas9 as an Obstacle to Persistent Genome Editing","abstract":"In vivo genome editing with CRISPR-Cas9 systems is garnering widespread attention and enthusiasm for possible treatment of genetic disorders. However, the consequences of potential immunogenicity of the bacterial Cas9 protein have been the subject of considerable speculation. In fact, a fraction of the human population is positive for pre-existing immunity to the most commonly used Cas9 variants, presumably a result of exposure to these microbes.1Charlesworth C.T. Deshpande P.S. Dever D.P. Camarena J. Lemgart V.T. Cromer M.K. Vakulskas C.A. Collingwood M.A. Zhang L. Bode N.M. et al.Identification of preexisting adaptive immunity to Cas9 proteins in humans.Nat. Med. 2019; 25: 249-254Crossref PubMed Scopus (435) Google Scholar, 2Wagner D.L. Amini L. Wendering D.J. Burkhardt L.M. Akyüz L. Reinke P. Volk H.D. Schmueck-Henneresse M. High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population.Nat. Med. 2019; 25: 242-248Crossref PubMed Scopus (202) Google Scholar, 3Ferdosi S.R. Ewaisha R. Moghadam F. Krishna S. Park J.G. Ebrahimkhani M.R. Kiani S. Anderson K.S. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes.Nat. Commun. 2019; 10: 1842Crossref PubMed Scopus (85) Google Scholar, 4Simhadri V.L. McGill J. McMahon S. Wang J. Jiang H. Sauna Z.E. Prevalence of Pre-existing Antibodies to CRISPR-Associated Nuclease Cas9 in the USA Population.Mol. Ther. Methods Clin. Dev. 2018; 10: 105-112Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar In vivo delivery of CRISPR-Cas9 is typically achieved with adeno-associated viral (AAV) vectors, which persist long-term in post-mitotic cells, further elevating concerns regarding sustained exposure to the foreign Cas9 antigen. Adaptive immune responses to Cas9 following AAV-CRISPR treatment have been observed in various mouse models with no pre-existing Cas9 immunity, but, interestingly, this does not seem to be an obstacle to long-term persistence of edited cells in these systems.5Nelson C.E. Wu Y. Gemberling M.P. Oliver M.L. Waller M.A. Bohning J.D. Robinson-Hamm J.N. Bulaklak K. Castellanos Rivera R.M. Collier J.H. et al.Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy.Nat. Med. 2019; 25: 427-432Crossref PubMed Scopus (223) Google Scholar, 6Thakore P.I. Kwon J.B. Nelson C.E. Rouse D.C. Gemberling M.P. Oliver M.L. Gersbach C.A. RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors.Nat. Commun. 2018; 9: 1674Crossref PubMed Scopus (90) Google Scholar, 7Chew W.L. Tabebordbar M. Cheng J.K. Mali P. Wu E.Y. Ng A.H. Zhu K. Wagers A.J. Church G.M. A multifunctional AAV-CRISPR-Cas9 and its host response.Nat. Methods. 2016; 13: 868-874Crossref PubMed Scopus (377) Google Scholar, 8Moreno A.M. Palmer N. Alemán F. Chen G. Pla A. Jiang N. Leong Chew W. Law M. Mali P. Immune-orthogonal orthologues of AAV capsids and of Cas9 circumvent the immune response to the administration of gene therapy.Nat. Biomed. Eng. 2019; 3: 806-816Crossref PubMed Scopus (57) Google Scholar However, early studies in mouse models have indicated that pre-existing immunity to Cas9 could limit gene editing efficacy.8Moreno A.M. Palmer N. Alemán F. Chen G. Pla A. Jiang N. Leong Chew W. Law M. Mali P. Immune-orthogonal orthologues of AAV capsids and of Cas9 circumvent the immune response to the administration of gene therapy.Nat. Biomed. Eng. 2019; 3: 806-816Crossref PubMed Scopus (57) Google Scholar In this issue of Molecular Therapy, Li et al.9Li A. Tanner M.R. Lee C.M. Hurley A.E. De Giorgi M. Jarrett K.E. Davis T.H. Doerfler A.M. Bao G. Beeton C. Lagor W.R. AAV-CRISPR Gene Editing Is Negated by Pre-existing Immunity to Cas9.Mol Ther. 2020; 28 (this issue): 1432-1441Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar provide valuable insights to this topic, although it is also important to acknowledge the caveats and limitations of this study in the broader context of therapeutic gen","journal":"Molecular Therapy","year":2020,"id":93285,"datarank":0.5570358100056463,"base_score":3.713572066704308,"endowment":3.713572066704308,"self_citation_contribution":0.5570358100056463,"citation_network_contribution":0.0,"self_endowment_contribution":0.5570358100056463,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9471,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":29946,"name":"Charles A. Gersbach","orcid":"0000-0003-1478-4013","position":1,"is_corresponding":false},{"id":412271,"name":"Veronica Gough","orcid":"0000-0002-8081-2329","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T22:30:54.208860Z","pmid":"32428441","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}