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

Objectives

To define shared and variant-specific mechanisms underlying LMNA-associated dilated cardiomyopathy (DCM) and identify therapeutic candidates using human stem cell–based models.

Background

Variants 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.

Methods

To 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.

Results

LMNA 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 Ca²⁺ 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.

Conclusion

Our findings reveal a shared disease mechanism across multiple LMNA variants driven by dysregulated Ca²⁺ handling. This work establishes a patient-specific drug discovery platform and identifies cyproheptadine as a promising therapeutic candidate for LMNA-associated dilated cardiomyopathy.

Highlights

• Patient-specific LMNA hiPSC-cardiomyocytes robustly recapitulate disease phenotypes, including nuclear defects, arrhythmias, and contractile dysfunction.

• Dysregulated calcium handling emerges as a unifying mechanism driving pathology across distinct LMNA variants.

• Variant-resolved analysis reveals both shared and mutation-specific molecular and functional signatures.

• High-throughput screening identifies cyproheptadine as a potent, broadly effective rescue agent across all tested LMNA variants.

• This work establishes a scalable precision medicine platform for rapid therapeutic discovery in inherited cardiomyopathies.