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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\u20134\u2009weeks, they trigger a \u223c60% 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 \u223c50\u201360% LDL-C lowering that lasts up to 6\u2009months (Phases II\u2013III 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.<\/jats:p>","DOI":"10.1093\/cvr\/cvz003","type":"journal-article","created":{"date-parts":[[2019,1,5]],"date-time":"2019-01-05T12:08:09Z","timestamp":1546690089000},"page":"510-518","source":"Crossref","is-referenced-by-count":86,"title":["Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies"],"prefix":"10.1093","volume":"115","author":[{"given":"Nabil G","family":"Seidah","sequence":"first","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM; Affiliated to the University of Montreal), Montreal, QC H2W1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annik","family":"Prat","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM; Affiliated to the University of Montreal), Montreal, QC H2W1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Pirillo","sequence":"additional","affiliation":[{"name":"Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan, Italy"},{"name":"IRCCS MultiMedica, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberico Luigi","family":"Catapano","sequence":"additional","affiliation":[{"name":"IRCCS MultiMedica, Milan, Italy"},{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 degli Studi di Milano, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Danilo","family":"Norata","sequence":"additional","affiliation":[{"name":"Center for the Study of Atherosclerosis, E. 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