Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia.
Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, Western Australia, Australia.
Curr Opin Lipidol. 2021 Dec 1;32(6):355-362. doi: 10.1097/MOL.0000000000000793.
Antisense oligomers (ASOs) have been available for decades: however, only recently have these molecules been applied clinically. This review aims to discuss the possible development of antisense-mediated splice correction therapies as precision medicines for familial hypercholesterolemic patients carrying mutations that compromise normal splicing of the low-density lipoprotein receptor (LDLR) gene transcript.
Three antisense drugs are currently being assessed in ongoing clinical trials for dyslipidemias, aiming to lower the plasma concentrations of lipoproteins that lead to end-organ damage, principally coronary artery disease. Although a handful of drugs may be applicable to many patients with familial hypercholesterolemia (FH), mutation-specific personalised antisense drugs may be even more effective in selected patients. Currently, there is no therapy that effectively addresses mutations in the LDLR, the major cause of FH. Many mutations in the LDLR that disrupt normal pre-mRNA processing could be applicable to splice correction therapy to restore receptor activity.
Precision medicine could provide long-term economic and social benefits if they can be implemented effectively and sustainably. Many mutations found in the LDLR gene could be amendable to therapeutic splice correction and we should consider developing a therapeutic ASO platform for these mutations.
目的综述：反义寡核苷酸（ASO）已经问世数十年，但直到最近，这些分子才被应用于临床。本文旨在讨论反义介导的剪接纠正疗法作为载脂蛋白 B100（apoB100）基因转录正常剪接受影响的家族性高胆固醇血症患者的精准药物的可能发展。
最新发现：目前有三种反义药物正在进行评估，用于治疗血脂异常，旨在降低导致靶器官损伤的脂蛋白（主要是冠状动脉疾病）的血浆浓度。虽然少数药物可能适用于许多家族性高胆固醇血症（FH）患者，但针对特定突变的个体化反义药物在选定患者中可能更有效。目前，尚无有效的治疗方法能有效治疗 LDLR 突变，LDLR 是 FH 的主要病因。许多破坏正常前体 mRNA 加工的 LDLR 突变可能适用于剪接纠正治疗以恢复受体活性。
总结：如果能有效地和可持续地实施，精准医学可能会带来长期的经济和社会效益。LDLR 基因中发现的许多突变可能适合治疗性剪接纠正，我们应该考虑为这些突变开发治疗性 ASO 平台。
