Disease-Modifying Therapeutic Approaches in a Gene-Edited Model of Timothy Syndrome

Timothy Syndrome is a rare genetic disease of the heart caused by a DNA mutation that increases the concentration of calcium ions in the heart, which are essential for proper electrical and mechanical activity of the heart. The disease causes life-threatening disorders of the heart rhythm and no effective treatment is available, leading to sudden cardiac death in early childhood. Our group has recently developed an animal model of Timothy Syndrome creating a genetically-modified pig that reproduces all the characteristics of the human disease. Studying the cells of our pig model allowed us to identify two novel therapeutic targets: Calcium-calmodulin Kinase II (CaMKII) and Calcineurin (CaN). Both of these proteins are activated by increased concentration of calcium ions and contribute to worsening the delicate balance of ions in the heart cells, thus facilitating the genesis of life-threatening disorders of the heart rhythm. In this project, we will test the hypothesis that novel therapies, which use drug inhibition of these two proteins, correct the alterations at the cell level. We shall use the heart cells from our pig model to investigate using sophisticated laboratory techniques the efficacy of the proposed therapies. To optimize the experiments, we will develop a mathematical model, which will predict the phenomena in the cells and will aid in identifying sideeffects. We expect to demonstrate the efficacy of these two therapies, paving the way for bringing these therapies to the clinic, and thus mitigating the risk of sudden cardiac death in patients with Timothy Syndrome.