{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:48:23Z","timestamp":1790927303035,"version":"4.1.0"},"reference-count":25,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              , the gene for the desmosomal protein plakophilin-2, are being enrolled in gene therapy trials designed to replace the defective allele via adeno-associated viral transduction of cardiac myocytes. Evidence from experimental systems and patients indicates that ventricular myocytes in\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              arrhythmogenic cardiomyopathy have greatly reduced electrical coupling at gap junctions and reduced Na\n              <jats:sup>+<\/jats:sup>\n              current density. In previous adeno-associated viral gene therapy trials, &lt;50% of ventricular myocytes have generally been transduced.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We used established computational models of ventricular cell electrophysiology to define the effects of varying levels of successful gene therapy on conduction in patients with\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              arrhythmogenic cardiomyopathy. Conduction velocity and development of conduction block were analyzed in tissue constructs composed of cells with levels of electrical coupling and Na\n              <jats:sup>+<\/jats:sup>\n              current density observed in experimental studies.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We observed a nonlinear relationship between conduction velocity and the proportion of transduced cells. Conduction velocity increased only modestly when up to 40% of myocytes were transduced. Conduction block did not occur in tissue constructs with moderate levels of uncoupling (0.10 or 0.15 of normal) as this degree of coupling was sufficient to allow electrotonic current to pass through diseased cells. Thus, low levels of transduction, likely to occur in phase 1 clinical trials, do not seem to pose a major safety concern. However, our models did not incorporate the potential effects of fibrosis and inflammation, both of which are presumably present in\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              arrhythmogenic cardiomyopathy patients undergoing gene therapy and could impact arrhythmogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              The extent of successful ventricular myocyte transduction anticipated to be achieved in\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              adeno-associated viral gene therapy trials will likely not restore conduction velocity to levels sufficient to decrease the risk of reentrant arrhythmias. Transduction efficiency of 60% to 80% would be required to restore conduction velocity to 50% of normal.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.124.013658","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T09:00:16Z","timestamp":1744189216000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Computational Modeling of Effects of\n            <i>PKP2<\/i>\n            Gene Therapy on Ventricular Conduction Properties in Arrhythmogenic Cardiomyopathy"],"prefix":"10.1161","volume":"18","author":[{"given":"Alessio","family":"Ostini","sequence":"first","affiliation":[{"name":"Department of Physiology (A.O., J.P.K.), University of Bern, Switzerland."},{"name":"Graduate School for Cellular and Biomedical Sciences (A.O.), University of Bern, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3233-2005","authenticated-orcid":true,"given":"Andr\u00e9 G.","family":"Kl\u00e9ber","sequence":"additional","affiliation":[{"name":"John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA (A.G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7561-4371","authenticated-orcid":true,"given":"Yoram","family":"Rudy","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Washington University, St. Louis, MO (Y.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-9457","authenticated-orcid":true,"given":"Jeffrey E.","family":"Saffitz","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (J.E.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-6962","authenticated-orcid":true,"given":"Jan P.","family":"Kucera","sequence":"additional","affiliation":[{"name":"Department of Physiology (A.O., J.P.K.), University of Bern, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","unstructured":"Lexeo Therapeutics. Gene therapy for ACM due to a PKP2 pathogenic variant. ClinicalTrials.gov ID NCT0610981."},{"key":"e_1_3_3_3_2","unstructured":"Rocket Pharmaceuticals Inc. A phase 1 dose-escalation trial of RP-A601 in subjects with PKP2 variant-mediated arrhythmogenic cardiomyopathy (PKP2-ACM). ClinicalTrials.gov ID NCT05885412."},{"key":"e_1_3_3_4_2","unstructured":"Tenaya Therapeutics. Open-label dose escalation study of safe and preliminary efficacy of TN-401 in adults with PKP2 mutation-associated ARVC (RIDGE-1). ClinicalTrials.gov ID NCT06228924."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1509267"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(97)00332-x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.06.033"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008008"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.003077"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165915"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2023.11.003"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0808138"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2012.11.018"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2008.00438.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.005105"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.68.6.1501"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.07.019"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00496"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2024.10.007"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00794.2003"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-5959-7_23"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1109\/TBME.1978.326270"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2412392"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI183441"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hroo.2023.09.006"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2022.12.004"}],"container-title":["Circulation: Arrhythmia and Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCEP.124.013658","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T13:42:14Z","timestamp":1748612534000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCEP.124.013658"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5]]},"references-count":25,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["10.1161\/CIRCEP.124.013658"],"URL":"https:\/\/doi.org\/10.1161\/circep.124.013658","relation":{},"ISSN":["1941-3149","1941-3084"],"issn-type":[{"value":"1941-3149","type":"print"},{"value":"1941-3084","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5]]},"assertion":[{"value":"2024-12-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}