Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, PA, USA.
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, PA, USA.
Atherosclerosis. 2023 Mar;368:14-24. doi: 10.1016/j.atherosclerosis.2023.01.010. Epub 2023 Jan 14.
Effective lipid lowering therapies are essential for the prevention of atherosclerosis and cardiovascular disease. Available treatments have evolved in both their efficacy and their frequency of administration, and currently include monoclonal antibodies, antisense oligonucleotides and siRNA approaches. However, an unmet need remains for more effective and long-lasting therapeutics. Gene editing permanently alters endogenous gene expression and has the potential to revolutionize disease treatment. Despite the existence of several gene editing approaches, the CRISPR/Cas9 system has emerged as the preferred technology because of its high efficiency and relative simplicity. This review provides a general overview of this promising technology and an update on the progress made towards the development of treatments of dyslipidemia. The recently started phase 1b gene editing clinical trial targeting PCSK9 in patients with heterozygous familial hypercholesterolemia and cardiovascular disease highlights how gene editing may become available to treat not only patients affected by rare disorders of lipid metabolism, but also patients that are difficult-to-treat or at high risk. Other targets like ANGPTL3, LDLR, and APOC3 are on track for further pre-clinical development. The identification of novel targets using electronic health record-linked biobanks and human sequencing studies will continue to expand the potential target pool, and clinical assessment of treated patients will provide essential efficacy and safety information on current strategies. Gene editing of genes regulating lipid metabolism holds promise as an exciting new therapeutic approach. However, since gene editing permanently alters a patient's genome, its therapeutic application in humans will require careful safety assessment and ethical considerations.
有效的降脂治疗对于预防动脉粥样硬化和心血管疾病至关重要。现有的治疗方法在疗效和给药频率方面都有了发展，目前包括单克隆抗体、反义寡核苷酸和 siRNA 方法。然而，仍然需要更有效和持久的治疗方法。基因编辑可永久性改变内源性基因表达，有可能彻底改变疾病的治疗方法。尽管存在几种基因编辑方法，但 CRISPR/Cas9 系统因其高效性和相对简单性而成为首选技术。本文综述了这一有前途的技术，并更新了开发治疗血脂异常方法的进展。最近开始的针对杂合家族性高胆固醇血症和心血管疾病患者的 PCSK9 的 1b 期基因编辑临床试验突出了基因编辑如何不仅可用于治疗受脂质代谢罕见疾病影响的患者，还可用于治疗难以治疗或高风险的患者。其他靶点如 ANGPTL3、LDLR 和 APOC3 也在进行进一步的临床前开发。使用电子健康记录相关的生物库和人类测序研究来鉴定新的靶点将继续扩大潜在的靶点库，对接受治疗的患者进行临床评估将提供关于当前策略的重要疗效和安全性信息。调节脂质代谢的基因的基因编辑有望成为一种令人兴奋的新治疗方法。然而，由于基因编辑永久性地改变了患者的基因组，因此其在人类中的治疗应用需要进行仔细的安全性评估和伦理考虑。
