hERG epitope mimic-decoy peptide corrects autoimmune-long QT syndrome in guinea pigs

Abstract Background The most investigated form of autoimmune-long-QT-syndrome (LQTS) is caused by circulating anti-Ro/SSA(Sjögren’s syndrome-related antigen-A)-52kD antibodies, which cross-react with a specific sequence of the human ether-à-go-go-related (hERG) potassium channel’s pore region, reducing the rapid inward-rectifying potassium current (IKr) density. We designed the scaffolded monobody decoy peptide-4, MDP4, comprised of a segment of the hERG extracellular pore region fused to a carrier monobody, aiming to neutralize the circulating anti-Ro/SSA-52kD antibodies cross-reacting with hERG. Methods MDP4 was designed using 3D-structure-based protein engineering and optimized via conformational search and energy minimization. QT-interval prolongation was induced in an established guinea pig model of autoimmune-associated LQTS via injection of Ro/SSA-52kD antigen over 15 days. Upon confirmation of QT-interval prolongation, MDP4 was administered, and electrocardiogram parameters were monitored for 30 days. IKr and action potentials were measured using the patch-clamp technique in guinea pig ventricular cardiomyocytes treated with IgG isolated from the sera of an anti-Ro/SSA-52kD antibody-positive patient with LQTS and Torsades de Pointes. Results Guinea pigs immunized with Ro/SSA-52kD antigen exhibit QTc prolongation and hERG-cross-reactive anti-Ro/SSA-52kD serum antibodies. In vivo treatment with MDP4 reverses QTc prolongation. MDP4 in vitro treatment of guinea pig ventricular myocytes also reverses IKr inhibition and action potential duration prolongation by anti-Ro/SSA-52kD antibodies from patients with LQTS and Torsades de Pointes. Conclusions Treatment with MDP4 results in recovery of both the QT-interval prolongation in vivo and IKr inhibition in vitro. MDP4 and other conceptually similar molecules may represent an innovative therapeutic approach for autoimmune LQTS in humans, and, prospectively, for other forms of arrhythmogenic autoimmune cardiac channelopathies.