Grant: Project Grant - PA: Nutrition, Metabolism and Diabetes

Blood level of bad cholesterol is directly correlated with the incidence of atherosclerosis and cardiovascular risk. Statins, currently the most prescribed drugs to reduce blood cholesterol, works by increasing a cholesterol receptor in the liver. About 42 million individuals at high cardiovascular risk in North America and Europe alone fail to achieve recommended cholesterol targets despite changing their diets, exercising and on maximally tolerated statin therapy and remain at high risk of a major cardiovascular event. Moreover, in a substantial number of patients, statins cause serious side effects. Therefore, there is a large unmet clinical need for affordable, safe and orally available add-on to statin therapies for patients at high cardiovascular risk. Our laboratory has designed innovative and highly performant screening platforms to enable the discovery of orally available drugs that robustly decrease blood cholesterol on top of statins. Here, a new class of small molecules that strongly decrease cholesterol levels in animal models, without any evidence of adverse events, has been identified and selected for further development and characterization. The primary objective of this project is to perform preclinical studies to improve potency and determine efficacy and safety of the drug candidates, either alone or in combination with statins in animal models. This project has the potential to lead to the identification of potent orally available cholesterol-lowering compounds to fulfill the urgent need of affordable medications for patients at high cardiovascular risk on maximally tolerated statin therapy.