Exploring Novel Treatment Options for Patients with LMNA-Related Cardiomyopathy Using Patient-Specific hiPSCs

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy, and a leading cause of heart failure, arrhythmias, and heart transplantation. Variants in LMNA account for 5-10% of cases of DCM, which in families with DCM and conduction system abnormalities increases to 30-45%. This makes LMNA the most common cause of DCM, however, the molecular pathways that link the variants in LMNA and DCM are still not fully understood. Hence, finding the best treatment for patients with LMNA-related DCM (LMNA-DCM) remains challenging. In previous studies, due to limited studies in the field and small study cohorts the variant/domain-specific phenotype and drug responses remain unclear. Moreover, due to lack of unbiased high-throughput screenings there is no drug designed specifically for LMNA-DCM. To address these issues, here we intend to study the variant-specific phenotype of a large cohort of LMNA-DCM using patient-specific human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). In Aim 1, we will generate an in vitro model of LMNA-DCM using patient-specific hiPSCs from ten LMNA-DCM patients harboring pathogenic LMNA variants with the aim to discover variant-specific phenotypes and disease-causing pathways. The hiPSC-CMs will be assessed based on their gene expression using RNA sequencing, electrophysiology using Syncropatch, and contractility and Ca2+ handling properties. This data will shed light on both variant-specific and common disease-causing pathways. In Aim 2a, we aim to unravel the mechanism of action of colchicine for treatment of LMNA-DCM. Colchicine is an FDA approved drug, which, inhibits microtubule assembly. Recently, a small clinical study suggested the beneficial effect of colchicine in reducing the burden of arrythmia and recovering the failing heart in LMNA-DCM. However, the mechanism by which colchicine improves LMNA-DCM is still unknown. To that end, hiPSC-CMs will be treated with different doses of colchicine and the optimal condition will be chosen based on the similarity of the gene expression and electrophysiological functions to the healthy group. This could unveil the mechanism of action of colchicine in a variant-specific manner. In Aim 2b we intend to discover drugs that target the LMNA-DCM disease-causing pathways by leveraging our patient-specific hiPSCs model and completing an in vitro unbiased large-scale drug screening. This could eventually lead to development of more efficient treatment for LMNA-DCM.