SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome

Abstract

Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS. The study sought to test the efficacy of novel, selective SGK1 inhibitors in induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQTS. The mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially compared with a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 SCN5A-P1332L variant-corrected isogenic control (IC). The SGK1-I1 therapeutic efficacy, compared with MEX, was tested for APD at 90% repolarization (APD90) shortening in SCN5A-P1332L, SCN5A-R1623Q, KCNH2-G604S, and KCNQ1-V254M iPSC-CMs using FluoVolt. The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared with its IC (646 ± 7 ms vs 482 ± 23 ms; P < .0001). MEX shortened the APD90 to 560 ± 7 ms (52% attenuation, P < .0001). SGK1-I1 shortened the APD90 to 518 ± 5 ms (78% attenuation, P < .0001) but did not shorten the APD90 in the IC. SGK1-I1 shortened the APD90 of the SCN5A-R1623Q iPSC-CMs (753 ± 8 ms to 475 ± 19 ms compared with 558 ± 19 ms with MEX), the KCNH2-G604S iPSC-CMs (666 ± 10 ms to 574 ± 18 ms vs 538 ± 15 ms after MEX), and the KCNQ1-V254M iPSC-CMs (544 ± 10 ms to 475 ± 11ms; P = .0004). Therapeutically inhibiting SGK1 effectively shortens the APD in human iPSC-CM models of the 3 major LQTS genotypes. These preclinical data support development of SGK1 inhibitors as novel, first-in-class therapy for patients with congenital LQTS.