B-PO01-007 THE EFFICACY OF MEXILETINE TREATMENT IN PATIENT-SPECIFIC RE-ENGINEERED CARDIOMYOCYTE MODELS OF LONG QT SYNDROME TYPE 1, 2, AND 3

Abstract

Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by prolongation of the cardiac action potential duration (APD) at the cellular level. Mexiletine (MEX) is an effective therapy in some patients with LQT3 and may have therapeutic efficacy in LQT2 also. However, the efficacy of MEX to shorten APD in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has not been tested. To test the efficacy of MEX in patient-specific re-engineered cardiomyocyte models of LQT1 (KCNQ1-V254M), LQT2 (KCNH2-G604S), and LQT3 (SCN5A-P1332L). iPSC-CMs were generated from a 29-year-old female (KCNQ1-V254M), a 16-year-old male (KCNH2-G604S), and an 8-year-old female (SCN5A-P1332L) with a history of syncope or sudden cardiac arrest. CRISPR-Cas9 G604S and P1332L variant-corrected isogenic controls were created to establish the curative level of APD shortening for LQT2 and LQT3 models. MEX’s therapeutic efficacy was tested for APD shortening in the 3 LQTS genotype-specific iPSC-CMs by recording the APD90 values 4 hours after treatment with 10 μM MEX using FluoVolt. The APD90 was prolonged significantly in KCNH2-G604S and SCN5A-P1332L iPSC-CMs compared to their isogenic controls (726 ± 8ms vs 425 ± 40ms in KCNH2-G604S, 654 ±8 ms vs 482 ± 23 ms in SCN5A-P1332L, p<0.0001). MEX shortened the APD90 on KCNH2-G604S iPSC-CMs from 726 ± 8ms to 605 ± 17 ms. MEX also shortened the average APD90 on SCN5A-P1332L to 570 ± 9 ms (49% attenuation relative to the isogenic control value). However, the APD90 in the KCNQ1-V254M iPSC-CMs was not significantly reduced. Clinically, MEX has shortened the P1332L-SCN5A positive patient’s QTc from 600 ms to 460 ms and the G604S-KCNH2 positive patient’s QTc from > 600 ms to 440 ms. The patient with KCNQ1-V254M has not been treated with MEX. This is the first ‘treatment-in-the-dish’ studies of patient-specific, re-engineered heart cells for all three major LQTS genotypes using MEX. Consistent with its clinical use in the patient herself, MEX normalized the pathological APD prolongation by nearly 50% in her LQT3 iPSC-CM model. Additionally, MEX effectively shortened the APD in the LQT2, but not in LQT1, cardiac cells.