A New-Generation Lipid-Lowering and Anti-Inflammatory siRNA Therapy for Atherosclerosis

ABSTRACT High levels of lipids, such as cholesterol, are a major risk factor of development of atherosclerotic cardiovascular disease (ASCVD), which promote plaque formation inside arteries. Despite the success of current lipid-lowering therapies (e.g., statins and PCSK9 inhibitors), ASCVD remains one leading cause of mortality. This may be due to the lack of effective and safe strategies that can concurrently reduce cholesterol synthesis in the liver and curb arterial inflammation in the atherosclerotic lesion. The long-term objective of this project is to develop a new lipid- lowering and anti-inflammatory siRNA therapy for more effective treatment of ASCVD, based on i) the discovery of new biological roles of Epsin endocytic adaptor proteins in hyperlipidemia and atherosclerosis by Dr. Chen (MPI) and ii) the development of long-acting, dual tissues-targeting siRNA lipid nanoparticles (LNPs) by Dr. Shi (MPI). We recently revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages, and that silencing macrophage Epsins leads to reduction of arterial inflammation and atherosclerotic plaque size. In new preliminary studies, we also discovered that Epsins in liver hepatocytes contribute to hyperlipidemia by promoting cholesterol synthesis and reducing low-density lipoprotein cholesterol (LDL-C) clearance. Thus, we expect that co-targeting of Epsins in both the liver and atherosclerotic lesion will effectively restrict hyperlipidemia and arterial inflammation in atherosclerosis. In parallel, we have lately developed a novel LNP platform that can dramatically prolong the duration of efficient siRNA silencing after a single intravenous injection, as compared to traditional siRNA LNPs. By further engineering our new siRNA LNPs, we can simultaneously silence Epsins in the atherosclerotic plaque and liver. In light of these promising data, we hypothesize that our long-acting siRNA LNP platform for dual tissues-targeting of Epsins could lead to development of a new, more potent lipid-lowering and anti-inflammatory therapy for ASCVD. Here, we aim to i) further optimize and understand the long-acting siRNA LNPs; ii) tune the siRNA LNP surface chemistry for sufficient co-targeting of the liver hepatocytes and lesional macrophages in vivo; and iii) systematically evaluate the efficacy and safety of our siEpsins LNPs in various mouse and rabbit models of atherosclerosis. The successful completion of this MPI project could facilitate the development of next-generation therapeutics for ASCVD.