A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs

Chiamaka U. Ukachukwu; Eric N. Jimenez-Vazquez; Shreya Salwi; Matthew Goodrich; Francisco G. Sanchez-Conde; Kate M. Orland; Abhilasha Jain; Lee L. Eckhardt; Timothy J. Kamp; David K. Jones

doi:10.1172/jci.insight.183444

A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs

Chiamaka U. Ukachukwu,¹ Eric N. Jimenez-Vazquez,¹ Shreya Salwi,¹ Matthew Goodrich,¹ Francisco G. Sanchez-Conde,¹ Kate M. Orland,² Abhilasha Jain,¹ Lee L. Eckhardt,² Timothy J. Kamp,² and David K. Jones¹

Published January 9, 2025 - More info

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Abstract

The hERG1 potassium channel conducts the cardiac repolarizing current, I_Kr. hERG1 has emerged as a therapeutic target for cardiac diseases marked by prolonged actional potential duration (APD). Unfortunately, many hERG1 activators display off-target and proarrhythmic effects that limit their therapeutic potential. A Per-Arnt-Sim (PAS) domain in the hERG1 N-terminus reduces IKr by slowing channel activation and promoting inactivation. Disrupting PAS activity increases IKr and shortens APD in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We thus hypothesized that the hERG1 PAS domain could represent a therapeutic target to reduce arrhythmogenic potential in a long QT syndrome (LQTS) background. To test this, we measured the antiarrhythmic capacity of a PAS-disabling single-chain variable fragment antibody, scFv2.10, in a hiPSC-CM line derived from a Jervell and Lange Nielsen syndrome (JLN) patient. JLN is a severe form of LQTS caused by autosomal recessive mutations in KCNQ1. The patient in this study carried compound heterozygous mutations in KCNQ1. Corresponding JLN hiPSC-CMs displayed prolonged APD and early after depolarizations (EADs). Disrupting PAS with scFv2.10 increased I_Kr, shortened APD, and reduced the incidence of EADs. These data demonstrate that the hERG1 PAS domain could serve as a therapeutic target to treat disorders of cardiac electrical dysfunction.

A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs

Chiamaka U. Ukachukwu,¹ Eric N. Jimenez-Vazquez,¹ Shreya Salwi,¹ Matthew Goodrich,¹ Francisco G. Sanchez-Conde,¹ Kate M. Orland,² Abhilasha Jain,¹ Lee L. Eckhardt,² Timothy J. Kamp,² and David K. Jones¹

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A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs

Chiamaka U. Ukachukwu,1 Eric N. Jimenez-Vazquez,1 Shreya Salwi,1 Matthew Goodrich,1 Francisco G. Sanchez-Conde,1 Kate M. Orland,2 Abhilasha Jain,1 Lee L. Eckhardt,2 Timothy J. Kamp,2 and David K. Jones1

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Chiamaka U. Ukachukwu,¹ Eric N. Jimenez-Vazquez,¹ Shreya Salwi,¹ Matthew Goodrich,¹ Francisco G. Sanchez-Conde,¹ Kate M. Orland,² Abhilasha Jain,¹ Lee L. Eckhardt,² Timothy J. Kamp,² and David K. Jones¹