Targeting trained immunity to prevent cardiovascular disease (TARGET-TRIM)

In mice, trained immunity contributes to the development of atherosclerosis. Interfering with this mechanism limits atherosclerosis. Together with Trained Therapeutix Discovery (TTxD), we identified compounds that can prevent trained immunity with the ultimate aim to prevent cardiovascular disease. TTxD is specialized to develop nanobiologics that specifically target myeloid cells to deliver chemical compounds to these cells.  

Cardiovascular diseases, such as myocardial infarction and stroke, are caused by atherosclerosis, a chronic inflammatory disorder of the vessel wall. Despite optimal treatment of cardiovascular risk factors, such as hypercholesterolemia, cardiovascular disease remains one of the most important causes of morbidity and mortality worldwide. Therefore, novel strategies to prevent atherosclerosis  and cardiovascular diseases are urgently needed.  

Innate immune cells, such as monocyte and macrophages, importantly regulate the pathophysiology of atherosclerosis. Recently, we discovered that innate immune memory, also called trained immunity, contributes to atherosclerosis. In this project, we aimed to identify compounds that can prevent the development of innate immune. In the first part, we screened a library of epigenetic modulators, and identified 4 that can effectively prevent trained immunity in human primary monocytes in vitro. Als, we showed effective prevention of trained immunity by a specific nanobiologic developed by TTxD. In the second part of the project, we developed a model of intermittent high fat diet-induced trained immunity. This accelerated atherosclerosis development and compounds that prevented trained immunity induction (e.g. anti-IL-1 antibodies) reduced atherosclerosis. The effect of the nanobiologic from TTxD on atherosclerosis is currently being evaluated.  

Deliverables include a list of effective compounds that can prevent trained immunity in the laboratory. In mice, we showed that interfering with trained immunity effectively reduces atherosclerosis. As such, the identified compounds could potentially be used to develop novel strategies to reduce CVD.