Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Curr Pharm Des. 2011;17(24):2575-91. doi: 10.2174/138161211797247550.
Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by high levels of plasma low density lipoproteins (LDL) and an increased risk of premature atherosclerosis and coronary heart disease. LDL receptor (LDLr) deficiency is the most prevalent cause of FH. Therefore, hepatocyte-directed LDLr gene transfer constitutes an important strategy for the treatment of this monogenetic disease. Nowadays, homozygous FH patients are treated with lipid-lowering drugs complemented by plasma or LDL apheresis. Liver transplantation can restore metabolism of apolipoprotein B containing lipoproteins, but requires lifelong immunosuppression to prevent organ rejection. Recently, significant progress in gene transfer technology has encouraged investigators to further develop LDLr gene transfer approaches for the treatment of FH. In experimental animal models of FH, LDLr overexpression following viral vector-based gene transfer has been shown to be associated with long-term stable correction of hyperlipidemia, with attenuation of atherosclerosis progression, and in certain cases even with lesion regression. The first part of this review provides a thorough overview of familial hypercholesterolemia including its diagnosis, lipoprotein metabolism, and current management. In the second part, we critically review experimental LDLr gene transfer studies demonstrating the progress that has been made from the initial proof of principle studies to recent investigations showing dramatic regression of atherosclerosis in experimental models.
家族性高胆固醇血症（FH）是一种遗传性代谢紊乱，其特征是血液中低密度脂蛋白（LDL）水平升高，且早发动脉粥样硬化和冠心病风险增加。LDL 受体（LDLr）缺乏是 FH 的最常见病因。因此，针对肝细胞的 LDLr 基因转移成为治疗这种单基因疾病的重要策略。目前，通过降脂药物联合血浆或 LDL 吸附疗法来治疗纯合子 FH 患者。肝移植可以恢复载脂蛋白 B 所含脂蛋白的代谢，但需要终身免疫抑制以防止器官排斥。最近，基因转移技术的显著进展促使研究人员进一步开发 LDLr 基因转移方法来治疗 FH。在 FH 的实验动物模型中，基于病毒载体的基因转移后 LDLr 的过表达与长期稳定纠正高脂血症、动脉粥样硬化进展的减轻有关，在某些情况下甚至与病变消退有关。这篇综述的第一部分全面概述了 FH，包括其诊断、脂蛋白代谢和当前的治疗方法。在第二部分中，我们批判性地回顾了 LDLr 基因转移的实验研究，这些研究展示了从最初的原理验证研究到最近的研究进展，即在实验模型中动脉粥样硬化显著消退方面取得的进展。
