CVON_GENIUS 2.0; granted 15-12-2017

Overall scientific summary

This GENIUS II proposal is built on the most promising targets identified in GENIUS I which we now aim to move towards clinical application. As such, GENIUS II builds on our unique integration of knowledge on dyslipidemia and the immune response as a consequence of dyslipidemia. The work is divided into four distinct work packages that represent the logical steps in drug development and accordingly each of the selected targets from GENIUS I to be studied was carefully placed into this track. Studies will include the actual testing of the effectiveness of small molecules, monoclonal antibodies and siRNA that modulate selected targets.The investigations will range from in vitro to in vivo analyses to improve mechanistic insight and druggability, and test effects on atherosclerosis. For five targets we already defined small molecules and a monoclonal that affect our targets. These drug leads will be further translated along toxicity studies and proof-of-pharmacology studies. We already identified three drugs affecting the current foremost targets of GENIUS I and we will study whether they can be efficiently applied to reduce atherosclerotic parameters in First-In-Human clinical studies. This will be possible through additional help of our industrial partners. In all studies, we will address gender specificity. Next to directly building on GENIUS I drug targets and drug leads, we want in this regard also take advantage of the most recent innovative developments to find new druggable targets in cells of male and female atherosclerotic lesions as well as in circulating cells (immunophenotyping and single cell sequencing.) This is also expected to lead to the identification of novel gender specific biomarkers that can facilitate identification of disease progression and improve diagnosis. Our talent program is designed in such a way that all young talent working on GENIUS II will gain insight in the opportunities and challenges of developing drugs for cardiovascular disease.

Overall, GENIUS II will focus on translating knowledge towards a clinical application.