{"doi":"10.1089/crispr.2024.0006","title":"Comparison of Gene-Editing Approaches for Severe Congenital Neutropenia-Causing Mutations in the <i>ELANE</i> Gene","abstract":"Safety considerations for gene therapies of inherited preleukemia syndromes, including severe congenital neutropenia (CN), are paramount. We compared several strategies for CRISPR/Cas9 gene editing of autosomal-dominant ELANE mutations in CD34 + cells from two CN patients head-to-head. We tested universal and allele-specific ELANE knockout, ELANE mutation correction by homology-directed repair (HDR) with AAV6, and allele-specific HDR with ssODN. All strategies were not toxic, had at least 30% editing, and rescued granulopoiesis in vitro . In contrast to published data, allele-specific indels in the last exon of ELANE also restored granulopoiesis. Moreover, by implementing patient-derived induced pluripotent stem cells for GUIDE-Seq off-target analysis, we established a clinically relevant “personalized” assessment of off-target activity of gene editing on the background of the patient’s genome. We found that allele-specific approaches had the most favorable off-target profiles. Taken together, a well-defined head-to-head comparison pipeline for selecting the appropriate gene therapy is essential for diseases with several gene editing strategies available.","journal":"The CRISPR Journal","year":2024,"id":447715,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":991349,"name":"Masoud Nasri","orcid":null,"position":1,"is_corresponding":false},{"id":1265820,"name":"Benjamin Dannenmann","orcid":"0000-0001-9850-8854","position":2,"is_corresponding":false},{"id":1266351,"name":"Perihan Mir","orcid":null,"position":3,"is_corresponding":false},{"id":1266352,"name":"Maksim Klimiankou","orcid":null,"position":6,"is_corresponding":false},{"id":1022523,"name":"Karl Welte","orcid":"0000-0001-5178-3074","position":7,"is_corresponding":false},{"id":990760,"name":"Julia Skokowa","orcid":"0000-0002-4399-2324","position":8,"is_corresponding":false},{"id":999040,"name":"Diana Amend","orcid":null,"position":9,"is_corresponding":false},{"id":1265819,"name":"Malte Ritter","orcid":"0000-0002-3670-7564","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:02:03.354708Z","pmid":"39436283","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":[]}