Targeting ApoB as a therapeutic approach for the treatment of dyslipidemia: the potential role of mipomersen

Clinical studies demonstrate that lowering LDL-C is associated with a decreased risk of cardiovascular disease. As such, LDL-C recommendations have been lowered over the last several years to keep in line with new clinical data. The currently available lipid-lowering modalities are insufficient to reach those goals for a small but significant percentage of the population. New lipid-lowering therapies that target a different pathway would therefore be of great utility in reaching these goals in high-risk individuals with severe hypercholesterolemia. Targeting efflux of lipids from the liver is an alluring pharmacological objective. Pharmacological inhibition of microsomal triglyceride transfer protein is highly efficacious at lowering LDL-C, but is associated with significant steatosis and fat malabsorption. Knockdown of ApoB, the protein required to produce VLDLs and LDLs, by antisense oligonucleotides is another approach for blocking the efflux of lipids from the liver. Studies in animal models and humans with high LDL-C levels suggest that blocking the synthesis of ApoB is not associated with the same degree of intestinal and hepatic side effects as observed with inhibitors of microsomal triglyceride transfer protein. Mipomersen, a sequence-specific antisense oligonucleotide targeting ApoB mRNA that is presently being tested in clinical trials, is a potentially useful adjunct therapy for individuals that are unable to reach their lipid-lowering goals with currently available lipid-lowering modalities.