Heart-on-chip technology as a novel screening system for lipid-lowering therapy
Functional lipoprotein lipase expression and modulation using heart-on-chip technology: towards a novel screening system for lipid-lowering therapy (LIP@HEART)
This project aims to develop a heart-on-chip screening platform for the identification of novel drugs that lower the risk of cardiovascular disease (CVD) by activating the enzyme lipoprotein lipase. The unique collaboration between the department of Applied Stem Cell Technologies (University of Twente), the division of Endocrinology (Leiden University Medical Center), and private partner River BioMedics assembles expertise on heart disease, lipid metabolism and organ-on-chip technology to fulfill this aim.
CVD are the number one cause of death worldwide, leading to 17,9 million deaths every year. Individuals with a high risk of developing CVD are nowadays mainly treated with cholesterol lowering drugs such as statins. Although disease risk can be lowered by a maximum of 40% in this way, a significant untreatable residual risk is left. Therefore, there is a big quest to find novel medicines.
The enzyme lipoprotein lipase (LPL) is a key player in lipid metabolism and has recently gained a lot of attention as novel druggable target for CVD risk reduction. Although identification of LPL-activating small molecules is eagerly awaited, screening of compound libraries is nowadays impossible, as it is extremely challenging to study LPL activity in an in vitro setting due to its complex mode of action, which requires direct crosstalk between endothelial cells and metabolically active tissue. Therefore, the objective is to use organ-on-chip technology to develop a predictable in vitro model for functional LPL activity. To this end, they will develop a microfluidic chip that allows for direct contact between 3D heart tissue and a monolayer of endothelial cells that line a microfluidic channel, using human induced pluripotent stem cells. By optimizing co-culturing conditions for optimal endothelial-cardiomyocyte crosstalk, they aim to maximize LPL activity.
If successful, their heart-on-chip model facilitates screening of large compound libraries to identify LPL-activating compounds that can be developed as novel drugs to combat CVD.