{"doi":"10.1101/2020.12.17.423314","title":"Co-opting regulation bypass repair (CRBR) as a gene correction strategy for monogenic diseases","abstract":"With the development of CRISPR/Cas9-mediated gene editing technologies, correction of disease- causing mutations has become possible. However, current gene correction strategies preclude mutation repair in post-mitotic cells of human tissues, and a unique repair strategy must be designed and tested for each and every mutation that may occur in a gene. We have developed a novel gene correction strategy, Co-opting Regulation Bypass Repair (CRBR), which can repair a spectrum of mutations in mitotic or post-mitotic cells and tissues. CRBR utilizes the non-homologous end-joining (NHEJ) pathway to insert a coding sequence (CDS) and transcription/translation terminators targeted upstream of any CDS mutation and downstream of the transcriptional promoter. CRBR gene repair results in simultaneous co-option of the endogenous regulatory region and bypass of the genetic defect. We demonstrated the potential of CRBR strategy for human gene therapy by rescuing a mouse model of the Wolcott-Rallison syndrome (WRS) with permanent neonatal diabetes caused by either large deletion or nonsense mutation in the PERK (EIF2AK3) gene. Additionally, we expressed a GFP CDS-terminator cassette that was integrated downstream of the human insulin promoter in cadaver pancreatic islets of Langerhans which paves the way for autologous cell-tissue replacement therapy for gene repair in beta cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127790,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"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":578034,"name":"Rebecca A. Bourne","orcid":null,"position":1,"is_corresponding":false},{"id":51388,"name":"Barbara C. McGrath","orcid":null,"position":2,"is_corresponding":false},{"id":578035,"name":"Alice Lin","orcid":null,"position":3,"is_corresponding":false},{"id":269934,"name":"Zifei Pei","orcid":"0009-0004-6484-6547","position":4,"is_corresponding":false},{"id":577301,"name":"Douglas R. Cavener","orcid":"0000-0002-1558-7137","position":5,"is_corresponding":false},{"id":577300,"name":"Jingjie Hu","orcid":"0000-0003-3534-1561","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-18T23:15:34.966380Z","pmid":null,"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":[]}