Structural and functional characterization of HERG potassium channels’ enhancers as a novel therapeutic strategy for Long QT Syndrome

Long QT syndrome (LQTS) is a rare inherited disease of the heart and one of the leading causes of sudden death in children and young adults. LQTS, which is caused by genetic defects in several genes coding for cardiac proteins, is diagnosed on the basis of a prolonged QT interval on the surface electrocardiogram. The treatment with beta-blocker drugs is an effective treatment for many patients affected by LQTS, but in some forms of LQTS the efficacy of beta-blockers is reduced. Among these, it is worth remembering the long QT syndrome type 2 (LQT2), type 3 (LQT3), and type 8 (LQT8). The latter, which is also known as Timothy syndrome, represents one of the rarest and most malignant forms of LQTS. The purpose of our research project is to identify innovative treatments for these severe variants of LQTS. We will therefore test the efficacy of a class of drugs that activate the function of cardiac potassium channels, the main players in determining the duration of the QT interval. These drugs, which are also known as "HERG activators", named after one of the most important potassium channels, will be partly synthesized by one of the participants in this research project and will be useful to shorten the abnormal duration of the QT interval in experimental models of LQTS. The "HERG activators" will initially be tested in two animal models of LQTS (a rodent with LQT2 and LQT3, and a pig model) and, subsequently, in cardiac myocytes engineered from the pluripotent cells of patients with LQT8. The pluripotent cells will be obtained from small samples of skin or from the urine of patients with LQT8 and will allow to study the effect of the "HERG activators" in the individual patients. We will select the most promising among the "HERG activators" tested in our experiments, and we will study the mechanism of action at the molecular level, thanks to the availability of cryoelectron microscopy techniques, a type of transmission electron microscopy in which the sample is studied at very low temperatures.