Functional High Throughput Drug Screening Reveals Cyproheptadine as a Novel Treatment for LMNA -related Cardiomyopathy

Abstract

ObjectivesTo define shared and variant-specific mechanisms underlying LMNA-associated dilated cardiomyopathy (DCM) and identify therapeutic candidates using human stem cell-based models. BackgroundVariants in the gene LMNA, encoding lamin A/C, cause 5-10% of dilated cardiomyopathies (DCM) and are strongly associated with heart failure and arrhythmias. Yet, the mechanisms by which LMNA variants drive disease and the distinction between shared and variant-specific phenotypes remain unclear. MethodsTo address this, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from six LMNA-DCM patients carrying three pathogenic variants (T150A, E381Afs*39, R527H) and from five healthy control patients. ResultsLMNA hiPSC-CMs exhibited nuclear membrane deformation, reduced beat rate, arrhythmias, and prolonged calcium transients. Transcriptomic and electrophysiological analyses revealed downregulation of cardiac genes and ion channels, with abnormal Ca{superscript 2} handling emerging as a shared disease mechanism. Leveraging a high-throughput functional assay, we performed an unbiased drug screen and identified cyproheptadine, an FDA-approved antihistamine, as the only compound to alleviate abnormal function across all LMNA variants. ConclusionOur findings reveal a shared disease mechanism across multiple LMNA variants driven by dysregulated Ca{superscript 2} handling. This work establishes a patient-specific drug discovery platform and identifies cyproheptadine as a promising therapeutic candidate for LMNA-associated dilated cardiomyopathy. HighlightsO_LIPatient-specific LMNA hiPSC-cardiomyocytes robustly recapitulate disease phenotypes, including nuclear defects, arrhythmias, and contractile dysfunction. C_LIO_LIDysregulated calcium handling emerges as a unifying mechanism driving pathology across distinct LMNA variants. C_LIO_LIVariant-resolved analysis reveals both shared and mutation-specific molecular and functional signatures. C_LIO_LIHigh-throughput screening identifies cyproheptadine as a potent, broadly effective rescue agent across all tested LMNA variants. C_LIO_LIThis work establishes a scalable precision medicine platform for rapid therapeutic discovery in inherited cardiomyopathies. C_LI