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Gene therapy approaches to increase INa have demonstrated potential benefits to prevent arrhythmias. However, the development of such therapies is hampered by the large size of sodium channels. In this study, SCN10A-short (S10s), a short transcript encoding the carboxy-terminal domain of the human neuronal sodium channel, was evaluated as a gene therapy target to increase INa and prevent arrhythmias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adeno-associated viral vector overexpressing S10s was injected into wild type and Scn5a-haploinsufficient mice on which patch-clamp studies, optical mapping, electrocardiogram analyses, and ischaemia reperfusion were performed. In vitro and in silico studies were conducted to further explore the effect of S10s gene therapy in the context of human hearts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Cardiac S10s overexpression increased cellular INa, maximal action potential upstroke velocity, and action potential amplitude in Scn5a-haploinsufficient cardiomyocytes. S10s gene therapy rescues conduction slowing in Scn5a-haploinsufficient mice and prevented ventricular tachycardia induced by ischaemia-reperfusion in wild type mice. S10s overexpression increased maximal action potential upstroke velocity in human inducible pluripotent stem cell-derived cardiomyocytes and prevented inducible arrhythmias in simulated human heart models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>S10s gene therapy may be effective to treat cardiac conduction abnormalities and associated arrhythmias.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf053","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T07:25:07Z","timestamp":1739431507000},"page":"1747-1762","source":"Crossref","is-referenced-by-count":20,"title":["<i>SCN10A-short<\/i>\n                    gene therapy to restore conduction and protect against malignant cardiac arrhythmias"],"prefix":"10.1093","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9244-4693","authenticated-orcid":false,"given":"Jianan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-834X","authenticated-orcid":false,"given":"Arie O","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, Amsterdam 1105 AZ ,","place":["The Netherlands"]},{"name":"Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-0869","authenticated-orcid":false,"given":"Ronald","family":"Wilders","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2070-6786","authenticated-orcid":false,"given":"Yingnan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University , Baltimore, MD 21218 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University , Baltimore, MD 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Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie R","family":"Boender","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, Amsterdam 1105 AZ ,","place":["The Netherlands"]},{"name":"PacingCure B.V. , Roetersstraat 35, Amsterdam 1018 WB ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mischa","family":"Klerk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam , Meibergdreef 15, Amsterdam 1105 AZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianne","family":"Fokkert","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam 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