Antisense Oligonucleotide Therapy for Calmodulinopathy.

IF 5.2 3区工程技术 Q2 ENERGY & FUELS

Energy & Fuels Pub Date : 2024-10-08 Epub Date: 2024-08-19 DOI:10.1161/CIRCULATIONAHA.123.068111

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

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引用次数: 0

Abstract

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 CALM1^F142L/+ 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 CALM1^F142L/+ 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 Calm1^N98S/+ 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.

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治疗钙调蛋白病的反义寡核苷酸疗法

背景：钙调蛋白病是一种罕见的遗传性心律失常综合征，由 CALM1、CALM2 或 CALM3 的显性杂合子变异引起，这些基因分别编码相同的 CaM（钙调蛋白）蛋白。我们假设，反义寡核苷酸（ASO）介导的受影响钙调蛋白基因耗竭将改善疾病表现，而其他两个钙调蛋白基因将保持 CaM 水平和功能：我们使用人类诱导多能干细胞衍生的心肌细胞和 CALM1 致病变体小鼠模型对这一假设进行了验证：结果：人类CALM1F142L/+诱导多能干细胞衍生的心肌细胞表现出动作电位延长，模拟了先天性长QT综合征。CALM1基因敲除或CALM1缺失ASO不会改变CaM蛋白水平，并使CALM1F142L/+诱导多能干细胞衍生心肌细胞的复极化持续时间正常化。同样，一种靶向小鼠Calm1的ASO在不影响CaM蛋白水平的情况下耗尽了Calm1转录本。这种ASO能缓解药物诱导的CalmN98S/+小鼠双向室性心动过速，而不会对心电或收缩功能产生有害影响：这些结果证明了靶向单个钙调蛋白基因的 ASO 是治疗钙调蛋白病的潜在有效且安全的疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Energy & Fuels 工程技术-工程：化工

CiteScore

9.20

自引率

13.20%

发文量

1101

审稿时长

2.1 months

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.