Rescue of Autoimmune-Associated Long QT Syndrome by Decoy Peptides

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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.