Raul H Bortolin, Farina Nawar, Chaehyoung Park, Michael A Trembley, Maksymilian Prondzynski, Mason E Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B Cavazzoni, Peter T Sage, Qing Ma, Robert D Whitehill, Dominic J Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A Kubli, Adam E Mullick, Vassilios J Bezzerides, William T Pu
{"title":"治疗钙调蛋白病的反义寡核苷酸疗法","authors":"Raul H Bortolin, Farina Nawar, Chaehyoung Park, Michael A Trembley, Maksymilian Prondzynski, Mason E Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B Cavazzoni, Peter T Sage, Qing Ma, Robert D Whitehill, Dominic J Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A Kubli, Adam E Mullick, Vassilios J Bezzerides, William T Pu","doi":"10.1161/CIRCULATIONAHA.123.068111","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in <i>CALM1</i>, <i>CALM2</i>, or <i>CALM3</i>, which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function.</p><p><strong>Methods: </strong>We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of <i>CALM1</i> pathogenic variants.</p><p><strong>Results: </strong>Human <i>CALM1</i><sup><i>F142L/+</i></sup> induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of <i>CALM1</i><sup><i>F142L/+</i></sup> induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine <i>Calm1</i> depleted <i>Calm1</i> transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in <i>Calm1</i><sup><i>N98S/+</i></sup> mice without a deleterious effect on cardiac electrical or contractile function.</p><p><strong>Conclusions: </strong>These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1199-1210"},"PeriodicalIF":35.5000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747850/pdf/","citationCount":"0","resultStr":"{\"title\":\"Antisense Oligonucleotide Therapy for Calmodulinopathy.\",\"authors\":\"Raul H Bortolin, Farina Nawar, Chaehyoung Park, Michael A Trembley, Maksymilian Prondzynski, Mason E Sweat, Peizhe Wang, Jiehui Chen, Fujian Lu, Carter Liou, Paul Berkson, Erin M Keating, Daisuke Yoshinaga, Nikoleta Pavlaki, Thomas Samenuk, Cecilia B Cavazzoni, Peter T Sage, Qing Ma, Robert D Whitehill, Dominic J Abrams, Chrystalle Katte Carreon, Juan Putra, Sanda Alexandrescu, Shuai Guo, Wen-Chin Tsai, Michael Rubart, Dieter A Kubli, Adam E Mullick, Vassilios J Bezzerides, William T Pu\",\"doi\":\"10.1161/CIRCULATIONAHA.123.068111\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in <i>CALM1</i>, <i>CALM2</i>, or <i>CALM3</i>, which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function.</p><p><strong>Methods: </strong>We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of <i>CALM1</i> pathogenic variants.</p><p><strong>Results: </strong>Human <i>CALM1</i><sup><i>F142L/+</i></sup> induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of <i>CALM1</i><sup><i>F142L/+</i></sup> induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine <i>Calm1</i> depleted <i>Calm1</i> transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in <i>Calm1</i><sup><i>N98S/+</i></sup> mice without a deleterious effect on cardiac electrical or contractile function.</p><p><strong>Conclusions: </strong>These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.</p>\",\"PeriodicalId\":10331,\"journal\":{\"name\":\"Circulation\",\"volume\":\" \",\"pages\":\"1199-1210\"},\"PeriodicalIF\":35.5000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747850/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCULATIONAHA.123.068111\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.123.068111","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Antisense Oligonucleotide Therapy for Calmodulinopathy.
Background: Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in CALM1, CALM2, or CALM3, which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function.
Methods: We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of CALM1 pathogenic variants.
Results: Human CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in Calm1N98S/+ mice without a deleterious effect on cardiac electrical or contractile function.
Conclusions: These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.
期刊介绍：
Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.
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