{"doi":"10.1101/2023.07.26.550728","title":"<i>In vivo</i> expansion of gene-targeted hepatocytes through transient inhibition of an essential gene","abstract":"Abstract Homology Directed Repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested “Repair Drive”, a novel method for improving targeted gene insertion in the liver by selectively expanding correctly repaired hepatocytes in vivo . Our system consists of transient conditioning of the liver by knocking down an essential gene, and delivery of an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive dramatically increases the percentage of correctly targeted hepatocytes, up to 25%. This resulted in a five-fold increased expression of a therapeutic transgene. Repair Drive was well-tolerated and did not induce toxicity or tumorigenesis in long term follow up. This approach will broaden the range of liver diseases that can be treated with somatic genome editing.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":396954,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":874196,"name":"So Hyun Park","orcid":"0000-0002-5283-4619","position":1,"is_corresponding":false},{"id":315970,"name":"Adam Castoreno","orcid":null,"position":2,"is_corresponding":false},{"id":811469,"name":"Mingming Cao","orcid":"0000-0002-4234-1175","position":3,"is_corresponding":false},{"id":241978,"name":"Ayrea Hurley","orcid":"0000-0002-8697-8610","position":4,"is_corresponding":false},{"id":874198,"name":"Lavanya Saxena","orcid":"0000-0001-6083-4013","position":5,"is_corresponding":false},{"id":332205,"name":"Marcel Chuecos","orcid":"0000-0002-1840-0948","position":6,"is_corresponding":false},{"id":666692,"name":"Christopher J. 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