Cegla Jaimini, Walji Shahenaz, Barton Lucy, Neuwirth Clare, Thompson Gilbert R
Lipids and Cardiovascular Risk Service, Department of Cardiology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom; Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom.
Lipids and Cardiovascular Risk Service, Department of Cardiology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.
JACC Adv. 2025 Apr 26;4(5):101708. doi: 10.1016/j.jacadv.2025.101708.
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.
纯合子家族性高胆固醇血症是一种罕见的、危及生命的遗传性疾病，其特征为严重的高胆固醇血症、黄瘤和动脉粥样硬化进展加速。未经治疗，它会在儿童期或青少年期导致主动脉根部和冠状动脉疾病。50年前引入的血浆置换标志着一种降低这些患者低密度脂蛋白的新型治疗方法，并最终使肌腱黄瘤消退、动脉粥样硬化进展停止且延长了寿命。在此，作者描述了从非选择性血浆置换到目前使用的各种形式的选择性脂蛋白分离术的转变，并探讨了当前他汀类药物时代降脂药物治疗的显著进展。这些进展包括抑制微粒体甘油三酯转移蛋白的小分子、抗前蛋白转化酶枯草溶菌素/克新9型和血管生成素样3的单克隆抗体，以及诸如短干扰RNA等基因导向疗法。最后，成簇规律间隔短回文重复序列介导的基因编辑作为一种一次性治疗方法具有很大前景，有可能永久性降低杂合子和纯合子家族性高胆固醇血症患者的低密度脂蛋白胆固醇。
