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":35,"journal":{"name":"Energy & Fuels","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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\":35,\"journal\":{\"name\":\"Energy & Fuels\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Energy & Fuels\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCULATIONAHA.123.068111\",\"RegionNum\":3,\"RegionCategory\":\"工程技术\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/19 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"ENERGY & FUELS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Energy & Fuels","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.123.068111","RegionNum":3,"RegionCategory":"工程技术","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/19 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ENERGY & FUELS","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：
Energy & Fuels publishes reports of research in the technical area defined by the intersection of the disciplines of chemistry and chemical engineering and the application domain of non-nuclear energy and fuels. This includes research directed at the formation of, exploration for, and production of fossil fuels and biomass; the properties and structure or molecular composition of both raw fuels and refined products; the chemistry involved in the processing and utilization of fuels; fuel cells and their applications; and the analytical and instrumental techniques used in investigations of the foregoing areas.
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