Therapeutic potential of antisense oligonucleotides for the management of dyslipidemia

Despite the availability of statins and other lipid-lowering drugs, cardiovascular disease is a leading cause of death in the USA and all industrialized nations, highlighting the need for additional therapeutic modalities. Antisense oligonucleotides, which are designed to alter the metabolism of RNA, are a new class of therapeutic agents that shows great promise for the treatment of dyslipidemias. A key advantage of the technology is the ability to selectively inhibit targets that cannot be modulated by traditional therapeutics such as structural proteins, transcription factors, lipoproteins, miRNAs and emerging factors that may influence lipid and lipoprotein metabolism. This review will describe the antisense technology platform, highlight preclinical data of antisense oligonucleotides targeting several risk factors that contribute to dyslipidemia and finally summarize the preclinical and clinical results relating to mipomersen, the most advanced cardiovascular antisense therapeutic agent, a second-generation 2' methoxyethyl gapmer inhibitor of human ApoB-100.