《生命科学》 2022, 34(10): 1264-1273

PCSK9的靶向基因治疗

陈彦好^1,2 , 丁秋蓉^1,*

¹中国科学院上海营养与健康研究所，中国科学院营养代谢与食品安全重点实验室，上海 200031 ²中国科学院大学，北京 100049

摘　要：

心血管疾病是全球非传染性疾病致死的主要原因。降低血液低密度脂蛋白胆固醇(low-density lipoprotein cholesterol, LDL-C) 是预防和治疗动脉粥样硬化引起的冠状动脉疾病的主要手段。人类遗传学研究发现携带PCSK9 功能缺失突变的个体血液LDL-C 含量显著降低，对心血管疾病有明显的保护作用。这使得PCSK9 成为基因编辑治疗以降低血液胆固醇的理想靶点。当前的研究证明在小鼠和非人灵长类动物中靶向敲除肝脏PCSK9 可显著降低血液低密度脂蛋白胆固醇，展现该基因治疗策略的发展前景。该文介绍了PCSK9 基因与心血管疾病的关系，并综述了基因组编辑技术的发展及其体内靶向PCSK9 基因以降低LDL-C 的研究进展。

通讯作者：丁秋蓉 , Email:qrding@sibs.ac.cn

Gene therapy targeting PCSK9

CHEN Yan-Hao^1,2 , DING Qiu-Rong^1,*

¹CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, ChineseAcademy of Sciences, Shanghai 200031, China ²University of Chinese Academy of Sciences, Beijing 100049, China

Abstract:

Cardiovascular diseases are the leading cause of deaths for non-communicable diseases globally. Lowering blood low-density lipoprotein cholesterol (LDL-C) has been  demonstrated to be the primary target to prevent and treat coronary artery disease (CVD). Human genetic studies have revealed the protective effects of the PCSK9 loss-of-function mutations, in that individuals carrying these mutations have significantly lower LDL-C and are protected from CVD. These studies have provided PCSK9 as an ideal target for gene therapy in the treatment of hypercholesterolemia. In addition, targeted knockout of liver PCSK9 in mice and non-human primates have been demonstrated to be able to significantly reduce blood  LDL-C. We here summarize the studies of PCSK9 in cardiovascular diseases, and the research progress of gene therapeutics targeting PCSK9 to reduce LDL-C.

Communication Author：DING Qiu-Rong , Email:qrding@sibs.ac.cn