Next generation advanced RNA inhibition therapy to treat cardiometabolic disease (LiverTarget)

RNA Therapeutics comprise a new rapidly expanding category of drugs including small interfering RNAs (siRNA) and messenger RNAs (mRNA) that have attracted tremendous interest recently due to their first in-class drug approvals and notable success of the mRNA vaccines in the clinic. Obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD), in turn, are highly prevalent devastating diseases of our times despite available medicines, accounting for more than one in two deaths worldwide. They frequently co-exist, in the same patient, and constitute independent risk factors for each other; yet, unified approaches directed against common targets and shared mechanisms are lacking. LiverTarget aims at exploiting Partners years of research in the field of cardiometabolic research, the identification of ceramide pathways and inflammatory targets, and the development of novel siRNA technologies and lipid formulations, to: 1. Generate innovative siRNA pools and synthetic mRNAs to regulate ceramide and inflammatory targets in the liver. 2. Formulate them in established human-approved liver-targeting lipid nanoparticles (LNP). 3. Determine their efficacy in vivo in preclinical mouse models of obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. 4. Complete the necessary safety and toxicology evaluation of the most promising lead candidates and prepare the preclinical evaluation dossier for the European Medicines Agency (EMA). This will result in a set of novel RNA-LNP formulations, directed against targets shared between ASCVD, diabetes and NAFLD, with demonstrated efficacy and toxicology, ready for further clinical development. It will also open up new directions of research towards the development innovative RNA therapeutics against liver targets for the treatment of cardiometabolic diseases, ultimately benefiting the patient, the society and the economy.