低密度脂蛋白(LDL)胆固醇浓度降低可预防动脉粥样硬化性心血管疾病。自然低胆固醇血症状态可以具有单基因病因,由PCSK9、ANGPTL3、MTTP、或APOB基因。在这次重点审查中,我们讨论了几种抑制这些基因产物靶向LDL胆固醇水平升高的新疗法的开发和临床应用。特别是,前蛋白转化酶枯草杆菌蛋白酶kexin9型(PCSK9)的抑制剂正在产生显着的临床影响,随后是血管生成素样3(ANGPTL3)的抑制剂。目前在临床上使用的是alirocumab和evolocumab,两种抗PCSK9单克隆抗体,inclisiran,一种阻止PCSK9翻译的小干扰RNA,evinacumab,抗ANGPTL3单克隆抗体和lomitapide,微粒体甘油三酯转移蛋白的小分子抑制剂。其他疗法处于开发的临床前或临床试验阶段;这些包括其他单克隆抗体,反义寡核苷酸,小分子抑制剂,模拟肽,adnectins,疫苗,和基因编辑疗法。特别是疫苗和基因编辑疗法具有巨大的潜力,可以潜在地赋予PCSK9或ANGPTL3活性的长期活性或提供单一治疗的终身敲低。受到单基因低胆固醇血症状态启发的生物疗法正成为有助于预防动脉粥样硬化性心血管疾病的有价值的工具。
Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.