TRAF-STOP therapy to reduCe inflammation in athERosclerosis.

ended

Atherosclerosis, the underlying cause of the majority of cardiovascular diseases, is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis induced cardiovascular disease risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Blocking the co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. However, long-term inhibition of CD40L or its receptor CD40 results in suppression of the immune system and poses a risk for thromboembolic events. Therefore, we focused on the downstream signaling pathways of CD40, and found that the interaction between CD40 and TNF-receptor-associated factor 6 (TRAF6) is the driving force for atherosclerosis. Using virtual ligand screening, we identified several small molecule inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. TRAF-STOPs significantly reduce (existing) atherosclerosis and treatment was well tolerated. The first toxicology results in mice show that there are no side effects. Here we pursue the hypothesis that TRAF-STOPs are excellent candidates to pass the translational pipeline towards a clinical application to treat atherosclerotic cardiovascular disease. Prof. Lutgens is one of the founders of the recently established start-up company Cartesio Therapeutics to be able to valorise our novel TRAF-STOPs. By the end of the PoC grant, we expect to have an oral drug available and to have completed toxicology and bio-distribution analysis in a large animal model (mini-pig) and have tested TRAF-STOPs in a pig model of atherosclerosis. This way, we hold a solid business case in our hands. The resulting business- and (pre-)clinical development plan and patent portfolio will then be ready for seed investment and venture capital funding.