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.
Novel strategies to target proprotein convertase subtilisin kexin 9 : beyond monoclonal antibodies / N.G. Seidah, A. Prat, A. Pirillo, A.L. Catapano, G.D. Norata. - In: CARDIOVASCULAR RESEARCH. - ISSN 0008-6363. - 115:3(2019), pp. 510-518.
|Titolo:||Novel strategies to target proprotein convertase subtilisin kexin 9 : beyond monoclonal antibodies|
NORATA, GIUSEPPE DANILO [Writing – Review & Editing] (Corresponding)
|Parole Chiave:||Gene silencing; LDL-C; Monoclonal antibodies; PCSK9; Physiology; Cardiology and Cardiovascular Medicine; Physiology (medical)|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Progetto:||Immunometabolic effects of apolipoprotein E: focus on the modulation of cholesterol metabolism in antigen presenting cells|
Proprotein convertase subtilisin/kexin type 9 (PCSK9): a link between lipotoxicity, mitochondrial dysfunction, and frailty-associated heart failure
Targeting epigenetic REPROGRamming of innate immune cells in Atherosclerosis Management and other chronic inflammatory diseases
|Data di pubblicazione:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/cvr/cvz003|
|Appare nelle tipologie:||01 - Articolo su periodico|