{"doi":"10.1161/circulationaha.120.051836","title":"Suppression-Replacement <i>KCNQ1</i> Gene Therapy for Type 1 Long QT Syndrome","abstract":"Background: Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the KCNQ1 -encoded K v 7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1. Methods: A dual-component suppression-and-replacement (SupRep) KCNQ1 gene therapy was created by cloning a KCNQ1 short hairpin RNA and a short hairpin RNA-immune KCNQ1 cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in KCNQ1 was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep. Results: In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type KCNQ1 and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune KCNQ1 as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls. Conclusions: This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced KCNQ1 to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of KCNQ1 . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.","journal":"Circulation","year":2021,"id":151035,"datarank":0.6698862177981877,"base_score":4.465908118654584,"endowment":4.465908118654584,"self_citation_contribution":0.6698862177981877,"citation_network_contribution":0.0,"self_endowment_contribution":0.6698862177981877,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":86,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9638,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":643456,"name":"C.S. John Kim","orcid":null,"position":1,"is_corresponding":false},{"id":642040,"name":"William A.C. Gendron","orcid":"0000-0002-2280-3133","position":2,"is_corresponding":false},{"id":262530,"name":"Wei Zhou","orcid":"0000-0001-7719-0859","position":3,"is_corresponding":false},{"id":636494,"name":"Dan Ye","orcid":"0000-0003-0619-7070","position":4,"is_corresponding":false},{"id":317432,"name":"J. Martijn Bos","orcid":"0000-0002-3635-2003","position":5,"is_corresponding":false},{"id":643457,"name":"David J. Tester","orcid":null,"position":6,"is_corresponding":false},{"id":250287,"name":"Michael A. Barry","orcid":"0000-0002-8568-5664","position":7,"is_corresponding":false},{"id":32887,"name":"Michael J. Ackerman","orcid":"0000-0002-8011-3333","position":8,"is_corresponding":false},{"id":642039,"name":"Steven M. Dotzler","orcid":"0000-0001-7834-8603","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:43:11.293086Z","pmid":"33504163","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":[]}