Li Zhi-Fan, Wu Na-Qiong
Cardiometabolic Center, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China.
Front Genet. 2022 Jun 9;13:911429. doi: 10.3389/fgene.2022.911429. eCollection 2022.
Refractory hypercholesterolemia (RH), including homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia, is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) despite existing cholesterol-lowering methods at maximal tolerable doses. Patients with RH have early onset and higher risk of atherosclerotic cardiovascular disease (ASCVD) under insufficient treatment. Therefore, it is urgent to seek new therapies to maintain the blood lipids in refractory hyperlipidemia at normal levels. Currently, new cholesterol-lowering strategies are on the market, not only at the protein level [i.e., bempedoic acid (inhibiting ATP-citrate lyase), alirocumab and evolocumab (monoclonal antibodies against PCSK9), evinacumab (monoclonal antibody against ANGPTL3)] but also at the transcript level [i.e., mipomersen (antisense oligonucleotide inhibiting ApoB), inclisiran (siRNA targeting PCSK9)], providing more options for RH patients to achieve their lipid-lowering targets. More RNA-based therapies targeting RH-related genes have been designed for the treatment. However, for a proportion of patients, especially those with LDLR deficiency, the available treatments are still insufficient. More recently, emerging genome engineering based on CRISPR/Cas9 techniques, and advanced delivery technologies such as lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, lipid nanoparticles, and exosomes are being rapidly developed and implemented as novel therapies for RH. Gene therapy targeting RH-related genes has been successfully conducted in cells, mice, and non-human primates with high efficacy in lipid lowering and good tolerability. Especially the new generation of genome editing technique, base editing, performed with ideal lipid-lowering effect and limited occurrence of unwanted results. Excitingly, a phase I/II clinical study of LDLR gene replacement has been recently completed in RH patients, likely to be employed in clinical practice in the future. Furthermore, new targets for cholesterol reduction such as REV-ERB, G protein-coupled receptor, Ubiquitin specific peptidase 20 are continually being developed. This narrative review updates recent advances in treatment for RH, summarizes related clinical trials and preclinical studies, especially on the prospect of gene therapy.
难治性高胆固醇血症（RH），包括纯合子家族性高胆固醇血症（HoFH）和复合杂合子家族性高胆固醇血症，其特征是尽管采用了最大耐受剂量的现有降胆固醇方法，但低密度脂蛋白胆固醇（LDL-C）水平仍然很高。RH患者发病早，在治疗不足的情况下发生动脉粥样硬化性心血管疾病（ASCVD）的风险更高。因此，迫切需要寻找新的疗法将难治性高脂血症患者的血脂维持在正常水平。目前，新的降胆固醇策略已上市，不仅有蛋白质水平的药物[即贝派地酸（抑制ATP-柠檬酸裂解酶）、阿利西尤单抗和依洛尤单抗（抗PCSK9单克隆抗体）、evinacumab（抗ANGPTL3单克隆抗体）]，还有转录水平的药物[即米泊美生（抑制载脂蛋白B的反义寡核苷酸）、inclisiran（靶向PCSK9的小干扰RNA）]，为RH患者实现降脂目标提供了更多选择。更多针对RH相关基因的基于RNA的疗法已被设计用于治疗。然而，对于一部分患者，尤其是那些存在低密度脂蛋白受体（LDLR）缺陷的患者，现有的治疗方法仍然不足。最近，基于CRISPR/Cas9技术的新兴基因组工程以及慢病毒载体、腺病毒载体、腺相关病毒载体、脂质纳米颗粒和外泌体等先进递送技术正在迅速发展并作为RH的新型疗法得以应用。针对RH相关基因的基因治疗已在细胞、小鼠和非人类灵长类动物中成功进行，具有高效的降脂作用和良好的耐受性。特别是新一代基因组编辑技术——碱基编辑，具有理想的降脂效果且不良结果发生率有限。令人兴奋的是，最近已在RH患者中完成了LDLR基因替代的I/II期临床研究，未来可能会应用于临床实践。此外，诸如REV-ERB、G蛋白偶联受体、泛素特异性肽酶20等新的降胆固醇靶点也在不断研发中。本叙述性综述更新了RH治疗的最新进展，总结了相关临床试验和临床前研究，特别是基因治疗的前景。
