{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:21:39Z","timestamp":1792524099519,"version":"4.5.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2021,4,6]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the\n              <jats:italic>KCNQ1<\/jats:italic>\n              -encoded K\n              <jats:sub>v<\/jats:sub>\n              7.1 potassium channel \u03b1-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              A dual-component suppression-and-replacement (SupRep)\n              <jats:italic>KCNQ1<\/jats:italic>\n              gene therapy was created by cloning a\n              <jats:italic>KCNQ1<\/jats:italic>\n              short hairpin RNA and a short hairpin RNA-immune\n              <jats:italic>KCNQ1<\/jats:italic>\n              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\n              <jats:italic>KCNQ1<\/jats:italic>\n              was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell\u2013derived 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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type\n              <jats:italic>KCNQ1<\/jats:italic>\n              and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune\n              <jats:italic>KCNQ1<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic>KCNQ1<\/jats:italic>\n              to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of\n              <jats:italic>KCNQ1<\/jats:italic>\n              . In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.120.051836","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T10:46:39Z","timestamp":1611830799000},"page":"1411-1425","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":86,"title":["Suppression-Replacement\n            <i>KCNQ1<\/i>\n            Gene Therapy for Type 1 Long QT Syndrome"],"prefix":"10.1161","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7834-8603","authenticated-orcid":true,"given":"Steven M.","family":"Dotzler","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.S. John","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.C.","family":"Gendron","sequence":"additional","affiliation":[{"name":"Department of Virology &amp; Gene Therapy, Vector and Vaccine Engineering Laboratory (W.A.C.G., M.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3635-2003","authenticated-orcid":true,"given":"J. Martijn","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic (J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic (J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Barry","sequence":"additional","affiliation":[{"name":"Department of Virology &amp; Gene Therapy, Vector and Vaccine Engineering Laboratory (W.A.C.G., M.A.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-3333","authenticated-orcid":true,"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (S.M.D., C.S.J.K., W.Z., D.Y., J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic (J.M.B., D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology (M.J.A.), 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