Leiden Academic Centre for Drug Research
At the division of Biopharmaceutics, we aim to develop and test new therapeutic approaches to limit or even prevent the development of atherosclerosis in order to reduce the number of acute cardiovascular syndromes such as myocardial infarction or stroke.
We do so by identifying genes responsible for the occurrence of cardiovascular disease by using genomics and specific gene knock-out technology, and by unraveling the immune mechanisms involved in atherosclerosis in order to develop novel experimental therapies to prevent and/or treat cardiovascular disease.
Cardiovascular diseases are still major causes of death in Western society, which results from the accumulation of lipids and inflammatory cells in the large arteries, leading to the development of atherosclerosis. The development of atherosclerotic plaques results from the complex interaction between lipids and lipoproteins, and the immune system. At the division of Biopharmaceutics, we aim to elucidate the mechanisms behind the development, progression and destabilization of the atherosclerotic plaque. It is for example well-established that genetic predisposition for atherosclerosis is related to lipoprotein disorders and inflammatory responses within the vessel wall. Using genetic screening, we aim to discover novel genes that are associated with the development of atherosclerosis. In addition, the excessive immune response that is initiated upon hyperlipidemia is one of our areas of investigation. Our goal is to use this information to develop novel therapeutic intervention strategies to halt the progression of atherosclerosis, stabilize the atherosclerotic plaque or even reverse plaque growth, leading to atherosclerotic plaque regression.
Macrophages and atherosclerotic lesions
The infiltration of monocytes in the arterial wall, their differentiation to macrophages, and the subsequent accumulation of cholesterol in these macrophages initiate the process of atherosclerosis. We study the importance of specific genes in macrophages for atherosclerotic lesion formation by means of bone marrow transplantation.
Immunotherapy to limit atherosclerosis
Atherosclerosis is a chronic inflammatory disease, and vaccination may be an attractive method to induce long lasting protection against endogenous factors that contribute to the development of atherosclerosis. In the past, we have shown that for example vaccination against modified LDL limits the development of atherosclerosis, and we are currently further expanding this research line. We also focus on the development of cellular immunotherapies to inhibit atherosclerosis, as we have shown using myeloid-derived suppressor cells and mesenchymal stem cells. Moreover, modulation of regulatory proteins of inflammation, including costimulatory pathways and cytokines, are explored as therapeutic strategies to prevent atherosclerosis.
Therapeutic intervention to enhance atherosclerotic plaque stability
Proteases degrade matrix molecules in the atherosclerotic plaque, thereby reducing atherosclerotic plaque stability. Mast cells, that contain proteases such as tryptase and chymase, have been identified at the site of rupture in specimens of human coronary arteries and their number in the plaque was seen to be predictive for future cardiovascular events. We have shown that episodes of systemic mast cell activation, during plaque progression in mice, leads to robust plaque expansion, while inhibition of chymase enhances plaque stability.