Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Curr Opin Lipidol. 2020 Jun;31(3):119-124. doi: 10.1097/MOL.0000000000000677.
Homozygous familial hypercholesterolemia (HoFH) is a rare disorder associated with early atherosclerotic disease due to impairment of the LDL receptor (LDLR) pathway. Because of their molecular defect, current treatment options have limited success in bringing HoFH patient to LDL-C target and morbidity and mortality remain high. We review current and upcoming therapies directed at HoFH, including gene therapy.
Recent real-world studies have confirmed the strength in lomitapide as a treatment adjunct to statins and other lipid-lowering therapies in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the treatment armamentarium offering an additional average reduction in LDL-C levels of 24% when added to background lipid-lowering therapies in this population. Although achieving adequate LDL-C levels in this population is difficult, there are several therapies on the horizon that may help more patients reach goal. Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to substantially reduce LDL-C of an average of 49%, independently of residual LDLR activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical trials. Adeno-associated virus-mediated gene transfer and gene editing techniques are in early clinical and preclinical development.
LDL-C lowering in HoFH patients remains very challenging. However, novel treatment options are emerging. Upcoming therapies directed at PCSK9 and ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may offer a unique opportunity to treat patients with a one-time treatment.
纯合子家族性高胆固醇血症（HoFH）是一种罕见的疾病，由于 LDL 受体（LDLR）途径受损，导致早发性动脉粥样硬化疾病。由于其分子缺陷，目前的治疗选择在将 HoFH 患者的 LDL-C 目标值降低方面收效有限，发病率和死亡率仍然很高。我们综述了针对 HoFH 的当前和即将出现的治疗方法，包括基因治疗。
最近的真实世界研究证实，洛美他派作为 HoFH 患者他汀类药物和其他降脂治疗的辅助治疗药物具有强大作用。前蛋白转化酶枯草溶菌素/激肽释放酶 9（PCSK9）抑制剂单克隆抗体的批准也为治疗手段增添了新的内容，当与该人群中的背景降脂治疗联合使用时，可额外平均降低 24%的 LDL-C 水平。尽管在该人群中达到足够的 LDL-C 水平很困难，但有几种治疗方法即将面世，可能会帮助更多患者达到目标。针对 ANGPTL3 的单克隆抗体依维莫司可显著降低 LDL-C，平均降低 49%，与 LDLR 活性的残留无关。针对 PCSK9 和 ANGPTL3 的 RNA 干扰在临床试验中显示出前景。腺相关病毒介导的基因转移和基因编辑技术处于早期临床和临床前开发阶段。
HoFH 患者的 LDL-C 降低仍然极具挑战性。然而，新的治疗选择正在出现。针对 PCSK9 和 ANPTL3 的即将出现的治疗方法可能会提供额外的 LDL-C 降低，以帮助患者达到足够的 LDL-C 水平。如果基因治疗和基因编辑技术被证明有效，可能会为一次性治疗患者提供独特的机会。
