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Cardiovasc Res. 2019 Mar 1;115(3):510-518. doi: 10.1093/cvr/cvz003.

Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies.

Author information

1
Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM; Affiliated to the University of Montreal), Montreal, QC H2W1R7, Canada.
2
Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy.
3
IRCCS MultiMedica, Milan, Italy.
4
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Abstract

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 2-4 weeks, they trigger a ∼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 ∼50-60% LDL-C lowering that lasts up to 6 months (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.

KEYWORDS:

Gene silencing; LDL-C; Monoclonal antibodies; PCSK9

PMID:
30629143
PMCID:
PMC6383053
[Available on 2020-03-01]
DOI:
10.1093/cvr/cvz003

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