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Despite the neurodegenerative disorder Alzheimer’s disease (AD) is the most common form of dementia in late adult life, there is currently no therapy available to prevent the onset or slow down the progression of AD. The progressive cognitive decline in AD correlates with a successive accumulation of cerebral amyloid-β (Aβ) due to impaired clearance mechanisms. A significant percentage is removed by low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transport across the blood–brain barrier (BBB) into the periphery. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to members of the low-density lipoprotein receptor protein family at the cell surface and targets them for lysosomal degradation, which reduces the number of functional receptors. However, the adverse impact of PCSK9 on LRP1-mediated brain Aβ clearance remains elusive. By using an established BBB model, we identified reduced LRP1-mediated brain-to-blood Aβ clearance due to PCSK9 across different endothelial monolayer in vitro. Consequently, the repetitive application of FDA-approved monoclonal anti-PCSK9 antibodies into 5xFAD mice decreased the cerebral Aβ burden across variants and aggregation state, which was not reproducible in brain endothelial-specific LRP1 −/− 5xFAD mice. The peripheral PCSK9 inhibition reduced Aβ pathology in prefrontal cortex and hippocampus–brain areas critically involved in memory processing—and prevented disease-related impairment in hippocampus-dependent memory formation. Our data suggest that peripheral inhibition of PCSK9 by already available therapeutic antibodies may be a novel and easily applicable potential AD treatment.

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.

This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among urban and rural residents in China, and elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for ASCVD. Considering the increasing burden of ASCVD, lipid management is of the utmost importance. In recent years, research on blood lipids has made breakthroughs around the world, hence a revision of Chinese guideline for lipid management is imperative, especially since the target lipid levels in the general population vary in respect to the risk of ASCVD. The level of LDL-C, which can be regarded as appropriate in a population without frisk factors, can be considered abnormal in people at high risk of developing ASCVD. As a result, the “Guidelines for the prevention and treatment of dyslipidemia\" were adapted into the “Chinese guideline for Lipid Management\" (henceforth referred to as the new guidelines) by an Experts’ committee after careful deliberation. The new guidelines still recommend LDL-C as the primary target for lipid control, with cardiovascular disease (CVD) risk stratification to determine its target value. These guidelines recommend that moderate intensity statin therapy in adjunct with a heart-healthy lifestyle, be used as an initial line of treatment, followed by cholesterol absorption inhibitors or/and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as necessary. The new guidelines provide guidance for lipid management across various age groups, from children to the elderly. The aim of these guidelines is to comprehensively improve the management of lipids and promote the prevention and treatment of ASCVD by guiding clinical practice.

Statins are known to lower levels of LDL cholesterol, protect against cardiovascular disease, and slightly increase the risk of type 2 diabetes. This analysis of genetic variants in 112,772 participants from 14 studies suggests that PCSK9 inhibitors may do the same. Monoclonal antibodies and other therapies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce low-density lipoprotein (LDL) cholesterol levels by approximately 50 to 60% in several randomized trials. 1 – 8 Whether lowering LDL cholesterol levels by inhibiting PCSK9 will reduce the risk of cardiovascular events and, like statins, also increase the risk of new-onset diabetes is unknown. 9 Exploratory and post hoc analyses of randomized trials have suggested that lowering LDL cholesterol levels by approximately 70 mg per deciliter (1.81 mmol per liter) with a PCSK9 inhibitor may reduce the risk of major cardiovascular events by up to . . .

Proprotein convertase subtilisin kexin 9 (PCSK-9)-targeting therapy has arisen as a new line for the treatment of hyperlipidemia. Inclisiran is a double-stranded small RNA molecule that works by blocking the transcription of PCSK-9, leading to a reduction of PCSK9 levels in the hepatocytes, resulting in an increased expression of low-density lipoprotein (LDL) receptors in the hepatocyte membrane and, as a consequence, it reduces the circulating levels of LDL cholesterol (LDL-C). Compared to the other LDL-C-lowering medications, such as statins, ezetimibe and PCSK-9 inhibitors, inclisiran proposes an infrequent dosing of twice a year, while simultaneously providing a significant reduction of LDL-C. Its prolonged effect offers an advantage against medication non-compliance, which is one of the main causes for not achieving LDL-C goals with standard therapy. Inclisiran has also proven to have a relatively safe profile with adverse effects occurring in similar frequency as with placebo. This review aims to present and discuss the current clinical and scientific data pertaining to the role of inclisiran in the management of hypercholesterolemia and treatment of cardiovascular disease (CVD).

Setmelanotide (IMCIVREE™, Rhythm Pharmaceuticals) is a melanocortin-4 (MC4) receptor agonist developed for the treatment of obesity arising from proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The drug has received its first approval in the USA for chronic weight management in patients 6 years and older with obesity caused by POMC, PCSK1 and LEPR deficiency and has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4 receptor pathway. Setmelanotide is also being developed in other rare genetic disorders associated with obesity including Bardet–Biedl Syndrome, Alström Syndrome, POMC and other MC4R pathway heterozygous deficiency obesities, and POMC epigenetic disorders. This article summarizes the milestones in the development of setmelanotide leading to this first approval for obesity caused by POMC, PCSK1 and LEPR deficiency.

Inclisiran, a small interfering RNA therapeutic, reduces hepatic synthesis of PCSK9. In two separate randomized trials, subcutaneous injections of inclisiran on day 1, day 90, and then every 6 months reduced LDL cholesterol levels by approximately 50% at month 17, with a modest excess of injection-site adverse events.

Neutrophil infiltration around lipotoxic hepatocytes is a hallmark of nonalcoholic steatohepatitis (NASH); however, how these 2 types of cells communicate remains obscure. We have previously demonstrated that neutrophil-specific microRNA-223 (miR-223) is elevated in hepatocytes to limit NASH progression in obese mice. Here, we demonstrated that this elevation of miR-223 in hepatocytes was due to preferential uptake of miR-223-enriched extracellular vesicles (EVs) derived from neutrophils as well other types of cells, albeit to a lesser extent. This selective uptake was dependent on the expression of low-density lipoprotein receptor (LDLR) on hepatocytes and apolipoprotein E (APOE) on neutrophil-derived EVs, which was enhanced by free fatty acids. Once internalized by hepatocytes, the EV-derived miR-223 acted to inhibit hepatic inflammatory and fibrogenic gene expression. In the absence of this LDLR- and APOE-dependent uptake of miR-223-enriched EVs, the progression of steatosis to NASH was accelerated. In contrast, augmentation of this transfer by treatment with an inhibitor of proprotein convertase subtilisin/kexin type 9, a drug used to lower blood cholesterol by upregulating LDLR, ameliorated NASH in mice. This specific role of LDLR and APOE in the selective control of miR-223-enriched EV transfer from neutrophils to hepatocytes may serve as a potential therapeutic target for NASH.

Lipoprotein(a) is similar to LDL cholesterol but contains apolipoprotein(a). A trial tested the effects of an oligonucleotide drug targeting apo(a) mRNA on lipoprotein(a) concentrations in patients with CVD.