Key result
Lipoprotein apheresis anchors HoFH treatment while novel therapies and gene editing promise further LDL-C reduction.
This review summarizes the evolution of treatments for homozygous familial hypercholesterolemia, from apheresis to novel pharmacotherapies and gene editing.
Apheresis remains HoFH standard now; leaves open optimal integration of gene editing pending trials.
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.
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Cegla et al. (2025) conducted a review in Homozygous Familial Hypercholesterolemia. Lipid-lowering therapies (apheresis, lomitapide, evinacumab, PCSK9 inhibitors) was evaluated. Lipoprotein apheresis remains a mainstay of treatment for homozygous familial hypercholesterolemia, while newer LDL receptor-independent therapies and gene editing hold promise for further LDL-C reduction.
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