Treatment of Homozygous Familial Hypercholesterolemia

Homozygous familial hypercholesterolemia is a rare, life-threatening, genetic disorder characterized by severe hypercholesterolemia, xanthomata, and accelerated atherosclerosis. Untreated, it results in aortic root and coronary artery disease in childhood or adolescence. The introduction of plasma exchange 50 years ago marked a novel therapeutic approach to reducing low-density lipoprotein in these patients and eventually resulted in resolution of tendon xanthomas, arrested progression of atherosclerosis, and increased longevity. Here the authors describe the transition from unselective plasma exchange to the various forms of selective lipoprotein apheresis now in use and consider the remarkable developments in lipid-lowering pharmacotherapy in the current poststatin era. These include small molecules inhibiting microsomal triglyceride transfer protein, monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 and angiopoietin-like-3, and gene-directed therapies such as short interfering RNA. Finally, clustered regularly interspaced short palindromic repeats-mediated gene editing holds great promise as a one-off treatment, with the potential to permanently lower low-density lipoprotein cholesterol in both heterozygous and homozygous patients with familial hypercholesterolemia.