Novel strategies to control lipid metabolism: Can the antisense drug mipomersen fulfill the unmet need?

摘要

Hypercholesterolemia is one of the most common diseases in the western world. It is also one of the most common reasons for atherosclerosis and other cardiovascular disorders. While a change in lifestyle and habits can improve high cholesterol levels in some cases, the pharmacological possibilities are not yet sufficient for the treatment of hypercholesterolemia. Standard in therapy is the administration of statins that inhibit the HMG-CoA reductase, a key enzyme in cholesterol synthesis in the liver. While primary hypercholesterolemia can often be controlled with lifestyle adaption and statin therapy, patients of familial hypercholesterolemia need LDL apheresis in most cases, since the available medications fail to reduce LDL-C levels sufficiently, even at maximum doses. The genetic disorder relies on mutations in the LDL receptor and leads to accumulation of LDL and lipoprotein(a) in plasma since the uptake of lipoproteins is dependent on the LDL receptor. This in turn causes xanthomas and severe cardiovascular disorders. Typical untreated plasma levels of LDL exceed 500 mg/dl and are not controllable with statins since even a reduction by 50% is not sufficient. While one homozygous patient with familial hypercholesterolemia appears in about one million people, the heterozygous form is much more prevalent (~1:500) [1]. Given the huge collective of patients with primary or familial hypercholesterolemia and the insufficient pharmacological agents, there is a strong unmet need for novel, effective and safe lipid-lowering drugs.