{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:50:54Z","timestamp":1793040654899,"version":"4.5.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">KCNH2<\/jats:italic>\n                      -mediated arrhythmia syndromes are caused by loss-of-function (type 2 long QT syndrome [LQT2]) or gain-of-function (type 1 short QT syndrome [SQT1]) pathogenic variants in the\n                      <jats:italic toggle=\"yes\">KCNH2<\/jats:italic>\n                      -encoded K\n                      <jats:sub>v<\/jats:sub>\n                      11.1 potassium channel, which is essential for the cardiac action potential.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      A dual-component \u201csuppression-and-replacement\u201d (SupRep)\n                      <jats:italic toggle=\"yes\">KCNH2<\/jats:italic>\n                      gene therapy was created by cloning into a single construct a custom-designed\n                      <jats:italic toggle=\"yes\">KCNH2<\/jats:italic>\n                      short hairpin RNA with ~80% knockdown (suppression) and a \u201cshort hairpin RNA-immune\u201d\n                      <jats:italic toggle=\"yes\">KCNH2<\/jats:italic>\n                      cDNA (replacement). Induced pluripotent stem cell-derived cardiomyocytes and their CRISPR-Cas9 variant-corrected isogenic control (IC) induced pluripotent stem cell-derived cardiomyocytes were made for 2 LQT2- (G604S, N633S) and 1 SQT1- (N588K) causative variants. All variant lines were treated with KCNH2-SupRep or non-targeting control short hairpin RNA (shCT). The action potential duration (APD) at 90% repolarization (APD\n                      <jats:sub>90<\/jats:sub>\n                      ) was measured using FluoVolt voltage dye.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      KCNH2-SupRep achieved variant-independent rescue of both pathologic phenotypes. For LQT2-causative variants, treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD\n                      <jats:sub>90<\/jats:sub>\n                      to near curative (IC-like) APD\n                      <jats:sub>90<\/jats:sub>\n                      levels (G604S IC, 471\u00b125 ms; N633S IC, 405\u00b155 ms) compared with treatment with shCT (G604S: SupRep-treated, 452\u00b176 ms versus shCT-treated, 550\u00b141 ms;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.0001; N633S: SupRep-treated, 399\u00b1105 ms versus shCT-treated, 577\u00b139 ms,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.0001). Conversely, for the SQT1-causative variant, N588K, treatment with KCNH2-SupRep resulted in therapeutic prolongation of the pathologically shortened APD\n                      <jats:sub>90<\/jats:sub>\n                      (IC: 429\u00b116 ms; SupRep-treated: 396\u00b161 ms; shCT-treated: 274\u00b112 ms).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      We provide the first proof-of-principle gene therapy for correction of both LQT2 and SQT1. KCNH2-SupRep gene therapy successfully normalized the pathologic APD\n                      <jats:sub>90<\/jats:sub>\n                      , thereby eliminating the pathognomonic feature of both LQT2 and SQT1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.122.003719","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T14:14:39Z","timestamp":1665670479000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Suppression and Replacement Gene Therapy for\n                    <i>KCNH2<\/i>\n                    -Mediated Arrhythmias"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1357-7656","authenticated-orcid":true,"given":"Sahej","family":"Bains","sequence":"first","affiliation":[{"name":"Medical Scientist Training Program (S.B., S.M.D.), Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7834-8603","authenticated-orcid":true,"given":"Steven M.","family":"Dotzler","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program (S.B., S.M.D.), Mayo Clinic, Rochester, MN."},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CS John","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4554-2244","authenticated-orcid":true,"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (D.J.T., M.J.A.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0619-7070","authenticated-orcid":true,"given":"Dan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN."},{"name":"Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic (D.J.T., M.J.A.), Mayo Clinic, Rochester, 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