According to the WHO an estimated number of 17 million people die of cardiovascular disease (CVD) each year, representing 30% of all deaths worldwide. Across the EU, a higher proportion of women (40.5%) die from CVD than men (34.4%) and healthcare costs currently exceed €169 billion and is rising in our ever aging population. Atherosclerosis is the main underlying pathology of CVD. Progression of atherosclerotic disease with subsequent thrombotic occlusion is the main mechanism for myocardial infarction and large artery stroke. In addition, heart failure is a major complication of myocardial infarction that results in a further decline of cardiac function and quality of life. Higher-income countries have higher rates of atherosclerotic CVD compared to those of lower-income countries. Although lipid lowering drugs have substantially decreased the incidence of CVD in 30% of patients, a substantial part of the population still suffers from CVD notwithstanding optimal lipid-modulating therapy. To tackle this residual risk attention is shifting towards new non-lipid modulating therapies. This re-emphasizes the multifactorial nature of the underlying atherosclerotic process, which, besides lipid accumulation, also comprises a substantial inflammatory component. The results of the recent CANTOS trial, showing for the first time that a targeted immune therapyreduces cardiovascular events in humans, emphasize the immune system’s importance in atherosclerosis and its clinical consequences. However, the trialed anti-IL1b therapy is not ideal as it increases infection risk. Therefore, a great need exists for the development of powerful atherosclerosis-specific immune-modulators that cause limited side effects.
The interaction between the different immune cells, and (subsequent) secretion of immune-regulatory and
activating cytokines and chemokines determines progression of atherosclerosis. Key players in modulating these complex immune interactions and responses are co-stimulatory molecules. We found that inhibition of the co-stimulatory molecules CD40L and CD40 is highly effective in reducing atherosclerosis, and in transforming dangerous vulnerable plaques into beneficial stable plaques. CD40L and CD40 antagonists are therefore known as the most potent preventers and stabilizers in a laboratory setting. Although CD40 and CD40L blocking antibodies are used in phase 2 trials for cancer, multiple sclerosis and Crohn’s disease, longterm treatment with these antibodies -as is needed for the treatment of atherosclerosis- is not feasible, because of the well-known risk of immunosuppression. Therefore, selective targeting of CD40 signaling intermediates that leave parts of CD40-signalling intact to preserve immunity is the preferred strategy. CD40 does not have intrinsic signal capabilities but needs adaptor molecules -TNF-receptor associated factors (TRAFs)- to exert signaling. We showed that CD40-TRAF6, and not CD40-TRAF2/3/5 interactions are the driving force in atherosclerosis. Genetic inhibition of CD40-TRAF6 interactions substantially inhibited atherosclerosis, but also reduced insulin resistance, all without causing immunosuppressive side effects. Thus, we consider inhibition of CD40-TRAF6 interactions a highly potent and selective therapeutic strategy for treating CVD.
In the context of my ongoing ERC Consolidator project CD40-INN, we identified small molecules that
inhibit the CD40-TRAF6, but not the CD40-TRAF2 interaction. These small moecules were tolerated, non-toxic, and were not immunosupressive in mice. Moreover, both TRAF-STOPs were able to reduce adipose tissue inflammation and insulin resistance in a diet-induced obesity model, ameliorated symptoms of multiple sclerosis and halted the initiation and progression of (existing) atherosclerosis. These small molecule inhibitors (SMIs) are powerful reagents to ameliorate CVD as they are well tolerated and non-toxic and do not cause immunosuppressive side effects.
In the PoC project TRACER, we have tested and optimized these existing small molecules for in human use. We have done elaborate toxicology analysis, pharmacodynamics and analyzed dose-dependent effects of this compound in small and large animal models (of atherosclerosis). We started a company, were able to obtain additional funding, and are currently optimizing our compound’s medicinal chemistry to make our CD40-TRAF6 inhibitors suitable for a first in human application.
