Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy

Nipun Malhotra; Omer Cavus; Michael J Wallace; John T Bobik; Kevin You; Sarah S Takenaka; Danielle Abdallah; Eleanor J Mohler; Steve Antwi-Boasiako; Nathaniel P Murphy; Holly Sucharski-Argall; Xianyao Xu; Stephen P Chelko; Thomas J Hund; Jason D Roberts; Peter J Mohler; Mona El Refaey

doi:10.1016/j.jacbts.2025.03.013

Evaluation of Tideglusib as a Disease Modifying Therapy in Murine Models of Arrhythmogenic Cardiomyopathy

JACC Basic Transl Sci. 2025 Aug;10(8):101281. doi: 10.1016/j.jacbts.2025.03.013.

Authors

Nipun Malhotra¹, Omer Cavus¹, Michael J Wallace², John T Bobik¹, Kevin You³, Sarah S Takenaka¹, Danielle Abdallah³, Eleanor J Mohler³, Steve Antwi-Boasiako³, Nathaniel P Murphy³, Holly Sucharski-Argall², Xianyao Xu³, Stephen P Chelko⁴, Thomas J Hund⁵, Jason D Roberts⁶, Peter J Mohler⁷, Mona El Refaey⁸

Affiliations

¹ The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart, and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Surgery/Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
² The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart, and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
³ The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart, and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
⁴ Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA.
⁵ The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart, and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Internal Medicine/Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA.
⁶ Population Health Research Institute, McMaster University, and Hamilton Health Sciences, Hamilton, Ontario, Canada.
⁷ The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart, and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Internal Medicine/Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
⁸ The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart, and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Surgery/Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. Electronic address: Mona.elrefaey@osumc.edu.

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease, and current pharmacological therapies are directed toward the management of electrical manifestations. To date, none address the underlying pathophysiology of this progressive condition. We evaluated the therapeutic efficacy of Tideglusib (TD) in Ank2 cardio-selective-knockout and homozygous desmoglein-2 mutant ACM mouse models. TD was able to prevent and reverse the reduced cardiac function in treated mice. Moreover, TD-treated adult mice displayed a reduction in ventricular arrhythmia following adrenergic stimulation. We provide compelling preclinical data for TD as a potential therapy for patients with ACM.

Keywords: GSK-3β; Tideglusib; ankyrin-B; arrhythmia; arrhythmogenic cardiomyopathy; cardiovascular disease; desmoglein-2.

Abstract

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