Targeting microsomal triglyceride transfer protein and lipoprotein assembly to treat homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a polygenic disease arising from defects in the clearance of plasma low-density lipoprotein (LDL), which results in extremely elevated plasma LDL cholesterol (LDL-C) and increased risk of atherosclerosis, coronary heart disease, and premature death. Conventional lipid-lowering therapies, such as statins and ezetimibe, are ineffective at lowering plasma cholesterol to safe levels in these patients. Other therapeutic options, such as LDL apheresis and liver transplantation, are inconvenient, costly, and not readily available. Recently, lomitapide was approved by the Federal Drug Administration as an adjunct therapy for the treatment of HoFH. Lomitapide inhibits microsomal triglyceride transfer protein (MTP), reduces lipoprotein assembly and secretion, and lowers plasma cholesterol levels by over 50%. Here, we explain the steps involved in lipoprotein assembly, summarize the role of MTP in lipoprotein assembly, explore the clinical and molecular basis of HoFH, and review pre-clinical studies and clinical trials with lomitapide and other MTP inhibitors for the treatment of HoFH. In addition, ongoing research and new approaches underway for better treatment modalities are discussed.