Abstract Body (Do not enter title and authors here): Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy. Thus far, more than 50 genes have been associated with DCM, of which LMNA (lamin A/C) is ranked as the most highly associated, representing 5-10% of the cases. Currently, in many cases of LMNA-related DCM (LMNA-DCM) the direct link between the LMNA variants and DCM is not fully understood. Furthermore, there are no pharmaceutical therapeutics designed specifically for LMNA-DCM patients. We have generated an in vitro model of LMNA-DCM using patient-specific human induced pluripotent stem cells (hiPSCs). Nine laminopathy patients, eight harboring five different pathogenic LMNA variants, and one with an EMD (emerin) variant were selected. Five healthy individuals were recruited as controls. hiPSCs from all the individuals were differentiated into cardiomyocytes, purified, and assessed based on their gene expression and function. Laminopathy hiPSC-derived cardiomyocytes (hiPSC-CMs) showed a significantly higher level of nuclear deformation compared to controls which was exacerbated after mechanical stress. RNA-sequencing analysis revealed more than 300 genes differentially expressed between controls and patients-derived hiPSC-CMs which were potentially associated with the DCM phenotype. Pathway enrichment analysis also confirmed prior findings that mTOR pathway genes are involved. Analysis of intracellular calcium dynamics revealed prolongation of calcium transient durations and arrhythmia in laminopathy hiPSC-CMs. Contractility analysis also revealed significantly lower beat rate and higher pulse width in hiPSC-CMs from LMNA variant carriers compared to controls. mTOR inhibition by sirolimus led to the correction of calcium transient abnormalities. These results suggested that high-throughput assays can be used to find drugs which can alleviate the abnormal cellular phenotype in LMNA hiPSC-CMs. Based on that, in an unbiased high-throughput functional drug screen analysis performed with hiPSC-CMs we tested 1280 FDA-approved drugs and identified one drug as the only compound to successfully correct the defective function of all LMNA hiPSC-CMs. In conclusion, our findings show significant electrophysiological and transcriptome differences between LMNA and control hiPSC-CMs, which can be attenuated by drug treatment. The in vitro functional trial performed in this study can provide human cell-based data for further development of effective treatments for LMNA-DCM.