KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2

BACKGROUND Patients with long QT syndrome (LQTS) are predisposed to life-threatening arrhythmias. A delay in

cardiac repolarization is characteristic of the disease. Pharmacotherapy, implantable cardioverter-defibrillators, and left

cardiac sympathetic denervation are part of the current treatment options, but no targeted therapy for LQTS exists to

date. Previous studies indicate that induced autoimmunity against the voltage-gated KCNQ1 K. channels accelerates

cardiac repolarization.

OBJECTIVES However, a causative relationship between KCNQ1 antibodies and the observed electrophysiological effects

has never been demonstrated, and thus presents the aim of this study.

METHODS The authors purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as singlechannel

recordings on Chinese hamster ovary cells overexpressing IKs channels. The effect of purified KCNQ1 antibodies

on human cardiomyocytes derived from induced pluripotent stem cells was then studied.

RESULTS The study demonstrated that KCNQ1 antibodies underlie the previously observed increase in repolarizing IKs

current. The antibodies shift the voltage dependence of activation and slow the deactivation of IKs. At the single-channel

level, KCNQ1 antibodies increase the open time and probability of the channel. In models of LQTS type 2 (LQTS2) using

human induced pluripotent stem cell-derived cardiomyocytes, KCNQ1 antibodies reverse the prolonged cardiac repolarization

and abolish arrhythmic activities.

CONCLUSIONS Here, the authors provide the first direct evidence that KCNQ1 antibodies act as agonists on IKs

channels. Moreover, KCNQ1 antibodies were able to restore alterations in cardiac repolarization and most importantly

to suppress arrhythmias in LQTS2. KCNQ1 antibody therapy may thus present a novel promising therapeutic

approach for LQTS2.