An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models

• Published in: The Journal of clinical investigation Vol. 135; no. 4
• Main Authors: Wang, Ping, Ahmed, Mahmoud Salama, Nguyen, Ngoc Uyen Nhi, Menendez-Montes, Ivan, Hsu, Ching-Cheng, Farag, Ayman B, Thet, Suwannee, Lam, Nicholas T, Wansapura, Janaka P, Crossley, Eric, Ma, Ning, Zhao, Shane Rui, Zhang, Tiejun, Morimoto, Sachio, Singh, Rohit, Elhelaly, Waleed, Tassin, Tara C, Cardoso, Alisson C, Williams, Noelle S, Pointer, Hayley L, Elliott, David A, McNamara, James W, Watt, Kevin I, Porrello, Enzo R, Sadayappan, Sakthivel, Sadek, Hesham A
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.02.2025
• Subjects: Animals; Calcium - metabolism; Cardiology; Cardiomyopathy, Dilated; Cardiomyopathy, Dilated - drug therapy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - pathology; Disease Models, Animal; Drug approval; Drug therapy; Genetic aspects; Humans; Mice; Mutation; Troponin T - chemistry; Troponin T - genetics; Troponin T - metabolism; United States; Heart failure; Cardiology; Genetic diseases
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI174081

Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell-derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.