Rescue of Autoimmune-Associated Long QT Syndrome by Decoy Peptides

PROJECT SUMMARY/ABSTRACT
Autoimmunity is increasingly recognized as a novel pathogenic mechanism for cardiac arrhythmias. Several
arrhythmogenic autoantibodies have been identified, cross-reacting with different types of surface proteins
critically involved in cardiomyocyte electrophysiology, primarily ion channels (autoimmune cardiac
channelopathies). Specifically, some of these autoantibodies can prolong the action potential duration,
leading to acquired long-QT syndrome (LQTS), a condition known to increase the risk of life-threatening
ventricular arrhythmias, particularly Torsades de Pointes (TdP) and sudden cardiac death. The most
investigated form of autoimmune LQTS is associated with the presence of circulating anti-Ro/SSA antibodies
(anti-Ro Abs), frequently found in patients with autoimmune diseases, but also in a significant proportion of
apparently healthy subjects in the general population. Accumulating evidence indicates that anti-Ro Abs can
markedly delay ventricular repolarization via a direct inhibitory cross-reaction with the extracellular pore region
of the human ether-à-go-go related gene K+ channel (hERG-K+), resulting in a higher propensity for anti-Ro
Abs-positive subjects to develop LQTS and ventricular arrhythmias/TdP. Recent population data demonstrate
that the risk of LQTS in subjects with circulating anti-Ro Abs is significantly increased, independent of a history
of overt autoimmune diseases. Here, we hypothesize that decoy peptides, designed to mimic the cross-
reactive B-cell epitope present on both Ro/SSA antigen and hERG-K+ channel S5-S6 pore region, can
neutralize anti-Ro Abs and thus normalize or prevent QTc prolongation. Such decoy peptides are therefore
innovative therapeutic tools for anti-Ro Abs induced LQTS, associated TdP and sudden cardiac death. In this
project, we aim to develop these tools and test the molecular, decoy peptides hypothesis with 3 aims: 1)
Validate the cross-reactive epitope hypothesis and optimize the decoy molecule into a valid biologic drug
candidate; 2) Normalize QTc prolongation by the administration of decoy peptides to an in vivo animal model of
autoimmune associated LQTS and 3) investigate the electrophysiological mechanisms by which the decoy
peptides normalize QTc prolongation on the surface ECG at the cardiomyicyte level.
Collectively, the new decoy peptides developed in this application may illuminate how anti-Ro Abs contribute to
the public health burden imposed by cardiac arrhythmias. In addition, this research could achieve new
understanding of pathophysiologic mechanisms of anti-Ro Abs and open a new therapeutic direction for
mitigating this burden, including the possibility of advancing our decoy peptide therapy towards a licensed
drug. Finally, a new concealed risk factor contributing to life-threatening ventricular arrhythmias and sudden
cardiac death events in the general population may be revealed and treated.

Grant Number: 5R01HL164415-04
NIH Institute/Center: NIH
Principal Investigator: Mohamed Boutjdir