Chan Dick C, Watts Gerald F
Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.
Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia; Lipid Disorders Clinic, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Western Australia, Australia.
Clin Ther. 2023 Nov;45(11):1034-1046. doi: 10.1016/j.clinthera.2023.07.008. Epub 2023 Jul 29.
High plasma concentrations of LDL and lipoprotein(a) (Lp[a]) are independent and causal risk factors for atherosclerotic cardiovascular disease (ASCVD). There is an unmet therapeutic need for high-risk patients with elevated levels of LDL-C and/or Lp(a). Recent advances in the development of nucleic acids for gene silencing (ie, triantennary N-acetylgalactosamine conjugated antisense-oligonucleotides [ASOs] and small interfering RNA [siRNA]) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and Lp(a) offer effective and sustainable therapies.
Related articles in the English language were identified through a search for original and review articles in the PubMed database using the following key terms: cardiovascular disease, dyslipidemia, PCSK9 inhibitors, Lp(a), LDL-cholesterol, familial hypercholesterolemia, siRNA, and antisense oligonucleotide and clinical trials (either alone or in combination).
Inclisiran, the most advanced siRNA-treatment targeting hepatic PCSK9, is well tolerated, producing a >30% reduction on LDL-C levels in randomized controlled trials. Pelacarsen is the most clinical advanced ASO, whereas olpasiran and SLN360 are the 2 siRNAs directed against the mRNA of the LPA gene. Evidence suggests that all Lp(a)-targeting agents are safe and well tolerated, with robust and sustained reduction in plasma Lp(a) concentration up to 70% to 90% in individuals with elevated Lp(a) levels.
Cumulative evidence from clinical trials supports the value of ASO and siRNA therapies targeting the synthesis of PCSK9 and Lp(a) for lowering LDL-C and Lp(a) in patients with established ASCVD or high risk of ASCVD. Further research is needed to examine whether gene silencing therapy could improve clinical outcomes in patients with elevated LDL and/or Lp(a) levels. Confirmation of the tolerability and cost-effectiveness of long-term inhibition of PCSK9 and Lp(a) with this approach is essential.
血浆中低密度脂蛋白（LDL）和脂蛋白(a) [Lp(a)]的高浓度是动脉粥样硬化性心血管疾病（ASCVD）独立的致病风险因素。对于低密度脂蛋白胆固醇（LDL-C）和/或Lp(a)水平升高的高危患者，存在未满足的治疗需求。针对前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）和Lp(a)的基因沉默核酸（即三触角N-乙酰半乳糖胺缀合反义寡核苷酸[ASO]和小干扰RNA[siRNA]）开发的最新进展提供了有效且可持续的治疗方法。
通过在PubMed数据库中使用以下关键词搜索原始文章和综述文章，确定英文相关文章：心血管疾病、血脂异常、PCSK9抑制剂、Lp(a)、LDL胆固醇、家族性高胆固醇血症、siRNA、反义寡核苷酸以及临床试验（单独或联合）。
Inclisiran是最先进的靶向肝脏PCSK9的siRNA治疗药物，耐受性良好，在随机对照试验中使LDL-C水平降低超过30%。Pelacarsen是临床进展最显著的ASO，而olpasiran和SLN360是两种针对LPA基因mRNA的siRNA。有证据表明，所有靶向Lp(a)的药物都是安全且耐受性良好的，在Lp(a)水平升高的个体中，可使血浆Lp(a)浓度强劲且持续降低达70%至90%。
临床试验的累积证据支持针对PCSK9和Lp(a)合成的ASO和siRNA疗法在降低已确诊ASCVD或ASCVD高危患者的LDL-C和Lp(a)方面的价值。需要进一步研究以检查基因沉默疗法是否能改善LDL和/或Lp(a)水平升高患者的临床结局。确认用这种方法长期抑制PCSK9和Lp(a)的耐受性和成本效益至关重要。
