{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:11:07Z","timestamp":1791414667520,"version":"4.3.3"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,6,24]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by irregular rhythms and right ventricular dysplasia. Sequence variations in desmosomal protein-encoding genes are linked to ARVC development. Effective treatments for ARVC are lacking. Whereas mRNA-based therapies have shown efficacy in humans, their therapeutic potential for inherited cardiomyopathies remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Whole-exome sequencing identified a novel\n                      <jats:italic toggle=\"yes\">DSC2<\/jats:italic>\n                      sequence variation causing autosomal recessive ARVC in a Chinese family with consanguineous marriage. Mouse models with\n                      <jats:italic toggle=\"yes\">Dsc2<\/jats:italic>\n                      sequence variation knock-in and constitutive knock-out were generated and analyzed using echocardiography and histology. Transcriptomic and biochemical analyses were conducted to explore ARVC mechanisms. Dsc2 mRNA delivered by intracardiac or transcoronary injection was assessed as a treatment for ARVC in\n                      <jats:italic toggle=\"yes\">Dsc2<\/jats:italic>\n                      knock-out mice. In addition, effects of Dsc2 mRNA were examined in a transverse aortic constriction mouse model with noninherited right ventricular systolic dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Dsc2<\/jats:italic>\n                      -deficient mice exhibited right ventricular dilation and dysfunction, mimicking human disease. Transcriptomic analysis identified\n                      <jats:italic toggle=\"yes\">Myl7<\/jats:italic>\n                      as the most downregulated gene in the right ventricles of\n                      <jats:italic toggle=\"yes\">Dsc2<\/jats:italic>\n                      -deficient mice, and its restoration by adeno-associated virus 9 rescued heart function. Dsc2 mRNA delivery, with or without lipid nanoparticle encapsulation, normalized heart size and function in\n                      <jats:italic toggle=\"yes\">Dsc2<\/jats:italic>\n                      -deficient mice. Reduced\n                      <jats:italic toggle=\"yes\">DSC2<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">MLC2a<\/jats:italic>\n                      expression was also noted in patients with noninherited dilated cardiomyopathy and in mice with transverse aortic constriction. A single dose of mRNA provided therapeutic effects lasting 2 to 3 months before declining.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Our study reveals novel mechanisms of ARVC caused by\n                      <jats:italic toggle=\"yes\">DSC2<\/jats:italic>\n                      loss of function, supported by human and mouse data. Loss of\n                      <jats:italic toggle=\"yes\">Myl7<\/jats:italic>\n                      contributes to reduced cardiac contractility in ARVC and dilated cardiomyopathy with right ventricular systolic dysfunction. Dsc2 mRNA treatment demonstrated significant therapeutic potential in ARVC and transverse aortic constriction models, providing a basis for future clinical applications.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.072340","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T05:00:19Z","timestamp":1744347619000},"page":"1780-1796","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2\u2013Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy"],"prefix":"10.1161","volume":"151","author":[{"given":"Yan","family":"Zou","sequence":"first","affiliation":[{"name":"Departments of Cardiology (Y. Zou, Z.L., J.J., Q.L., J.M.J.W., K.J., X.R., Y. Zhang, C.H., Y.X., H.G., J. Lin, J.G., Y.D.), Shanghai Institute of Cardiovascular Diseases"},{"name":"Shanghai RNACure Biopharma Co, Ltd, Shanghai, China (Y. Zou, J. Lu, H. Yu)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lu","sequence":"additional","affiliation":[{"name":"Shanghai RNACure Biopharma Co, Ltd, Shanghai, China (Y. Zou, J. Lu, H. Yu)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6608-6276","authenticated-orcid":true,"given":"Zhipeng","family":"Lian","sequence":"additional","affiliation":[{"name":"Departments of Cardiology (Y. Zou, Z.L., J.J., Q.L., J.M.J.W., K.J., X.R., Y. Zhang, C.H., Y.X., H.G., J. Lin, J.G., Y.D.), Shanghai Institute of Cardiovascular Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Jia","sequence":"additional","affiliation":[{"name":"Departments of Cardiology (Y. Zou, Z.L., J.J., Q.L., J.M.J.W., K.J., X.R., Y. Zhang, C.H., Y.X., H.G., J. Lin, J.G., Y.D.), Shanghai Institute of Cardiovascular Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Shen","sequence":"additional","affiliation":[{"name":"BGI-Shenzhen, Shenzhen, China (J.S., H. Yang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianhe","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Cardiology (Y. Zou, Z.L., J.J., Q.L., J.M.J.W., K.J., X.R., Y. Zhang, C.H., Y.X., H.G., J. Lin, J.G., Y.D.), Shanghai Institute of Cardiovascular Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7181-1642","authenticated-orcid":true,"given":"Jennifer Ming Jen","family":"Wong","sequence":"additional","affiliation":[{"name":"Departments of Cardiology (Y. Zou, Z.L., J.J., Q.L., J.M.J.W., K.J., X.R., Y. Zhang, C.H., Y.X., H.G., J. 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