期刊
CARDIOVASCULAR RESEARCH
卷 115, 期 3, 页码 510-518出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvz003
关键词
PCSK9; LDL-C; Monoclonal antibodies; Gene silencing
资金
- Canadian Institutes of Health Research grants Foundation Scheme [148369]
- Canada Research Chair [231335]
- Fondation Leducq [13CVD03]
- Fondazione Cariplo [2015-0524, 2015-0564, 2016-0852]
- H2020 REPROGRAM [PHC-03-2015/667837-2]
- Ministero della Salute [GR-2011-02346974]
- Aspire Cardiovascular Grant [2016-WI218287]
Since the discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of low-density lipoprotein cholesterol (LDL-C) in 2003, a paradigm shift in the treatment of hypercholesterolaemia has occurred. The PCSK9 secreted into the circulation is a major downregulator of the low-density lipoprotein receptor (LDLR) protein, as it chaperones it to endosomes/lysosomes for degradation. Humans with loss-of-function of PCSK9 exhibit exceedingly low levels of LDL-C and are protected from atherosclerosis. As a consequence, innovative strategies to modulate the levels of PCSK9 have been developed. Since 2015 inhibitory monoclonal antibodies (evolocumab and alirocumab) are commercially available. When subcutaneously injected every 2-4weeks, they trigger a approximate to 60% LDL-C lowering and a 15% reduction in the risk of cardiovascular events. Another promising approach consists of a liver-targetable specific PCSK9 siRNA which results in approximate to 50-60% LDL-C lowering that lasts up to 6months (Phases II-III clinical trials). Other strategies under consideration include: (i) antibodies targeting the C-terminal domain of PCSK9, thereby inhibiting the trafficking of PCSK9-LDLR to lysosomes; (ii) small molecules that either prevent PCSK9 binding to the LDLR, its trafficking to lysosomes or its secretion from cells; (iii) complete silencing of PCSK9 by CRISPR-Cas9 strategies; (iv) PCSK9 vaccines that inhibit the activity of circulating PCSK9. Time will tell whether other strategies can be as potent and safe as monoclonal antibodies to lower LDL-C levels.
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