Cardiovascular disease and its atherosclerotic complications of heart attack and stroke constitute the number-one cause of death in the world, affecting both genders and becoming more and more prevalent. For instance, in Europe, just Coronary Heart Disease (CHD) accounts for 42% and 38% of deaths in women and men, respectively, before the age of 75. Thus, CHD remains a prevalent and high burden disease with unmet medical needs in Europe. In addition to the humane point of view and lives lost, CHD poses a problem for the EU economy costing over €210 billion a year according to European cardiovascular disease statistics 2017 and are projected to rise further with both the ageing population and the cost of novel treatments.
Atherosclerotic cardiovascular disease (ASCVD) frequently co-exists with obesity, insulin resistance, diabetes mellitus and/or non-alcoholic fatty liver disease (NAFLD), all of which constitute independent and inter-related risk factors for its development, severity and acute clinical complications of heart attack and stroke. Diabetes increases the risk for ASCVD by more than 2-fold. An important risk factor for both ASCVD and diabetes is NAFLD. NAFLD is the most prevalent cause of liver disease worldwide affecting one in four people. In addition to increased cardiovascular event risk, NAFLD can itself lead to life threatening conditions by progressing to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. These above-mentioned conditions are the key features of the cardiometabolic disease that represents one of the most serious health challenges of the 21st century.
Given the high prevalence of the cardiometabolic disease, the prevention of morbidity and mortality is a major public health objective and the focus of this project. Our strategy is to develop liver-targeted treatments for metabolic disease using innovative siRNA pools and synthetic mRNAs aiming to reduce both lipid and inflammation load. By doing so our approach aims to lower the risk of complications resulting from metabolic diseases, such as atherosclerosis, myocardial infarction, heart failure, kidney damage, liver failure and even death. These new treatments will complement current medications offered to patients suffering from metabolic disease and will further improve treatment outcomes. In the long-term, the results of this pioneering project will reduce disease burden and especially the more serious complications such as myocardial infarction and stroke, progression of liver disease to NASH and fatalities. Tackling cardiometabolic disease will save productive quality life-years and will also lead to significant increase in productivity and health economic savings.
One of the attractive liver targets is the machinery controlling the production of ceramides. Research has shown that specific ceramide lipids are closely linked to the manifestation of CHD, ASCVD, stroke and diabetes. Additional research on ceramides in animal models has shown that elevated levels of ceramides are involved in the pathogenesis of obesity, steatosis, type 2 diabetes, NASH, atherosclerosis, and major adverse cardiac events.
Ceramides are known to be highly bioactive lipids that have an important role in many cellular functions such as apoptosis and inflammation. The ceramide synthetic machinery in the liver is highly active and strongly contributes to the systemic ceramide balance via lipoprotein mediated lipid trafficking, affecting biology at distant body sites beyond the liver. Therefore, the project is interested in the ceramide synthetic pathway in the liver, as it offers multiple targets for drug development and has the potential to lead to rational new therapies for some of the most devastating and lethal diseases of our times.
