Vaccines Targeting PSCK9 for the Treatment of Hyperlipidemia

Tóth, Štefan; Pella, Dominik; Fedačko, Ján

doi:10.1007/s40119-020-00191-6

Cited by 14 publications

(22 citation statements)

References 44 publications

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“…Studies have shown that gain-of-function mutations of PCSK9 cause hyperlipidemia and early onset coronary heart disease, whereas loss-of-function mutations result in low plasma cholesterol levels and protection against coronary heart disease without apparent negative consequences. PCSK9 interacts with LDLR epidermal growth factor-like repeat A domain and induces its lysosomal degradation, thereby regulates plasma cholesterol levels. − Therefore, inhibition of PCSK9 is being pursued as an approach to reduce plasma LDL cholesterol and TG levels. , …”

Section: Discussionmentioning

confidence: 99%

Amino Acid Conjugates of 2-Mercaptobenzimidazole Ameliorates High-Fat Diet-Induced Hyperlipidemia in Rats via Attenuation of HMGCR, APOB, and PCSK9

et al. 2022

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Purpose: This study was designed to explore the antihyperlipidemic effects of amino acid derivatives of 2-mercaptobenzimidazole (4J and 4K) in high-fat diet (HFD)-fed rats. Methods: Male Sprague-Dawley rats were divided into nine groups which received either standard diet or HFD for 28 days. Blood samples were taken on 27th day from HFD-fed rats to ensure hyperlipidemia. HFD-induced hyperlipidemic rats later received daily dosing of either vehicle or simvastatin (SIM; 20 mg/kg) or 4J/4K compounds (10, 20, and 30 mg/kg) for 12 consecutive days. On 40th day, animals were sacrificed, and blood samples were collected for the determination of serum lipid profile and liver function parameters. Liver samples were harvested for histopathological, antioxidant, and qPCR analyses. Molecular docking of tested compounds with HMGCR was also performed to assess the binding affinities. Results: 4J and 4K dose dependently decreased serum total cholesterol, triglycerides, low-density lipoprotein, very low-density lipoproteins, alanine transaminase (ALT), and aspartate aminotransferase (AST) levels while significantly alleviated high-density lipoproteins. However, SIM failed to reduce AST and ALT levels. Moreover, tested compounds displayed antioxidant effects by inducing superoxide dismutase and glutathione levels. Histopathology data also displayed protective effects of 4J and 4K against HFD-induced fatty changes and hepatic damage. In addition, 4J and 4K downregulated transcript levels of HMGCR, APOB, PCSK9, and VCAM1, and molecular docking analysis also supported the experimental data. Conclusion: It is conceivable from this study that 4J and 4K exert their antihyperlipidemic effects by modulating multiple targets regulating lipid levels.

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Section: Discussionmentioning

confidence: 99%

Amino Acid Conjugates of 2-Mercaptobenzimidazole Ameliorates High-Fat Diet-Induced Hyperlipidemia in Rats via Attenuation of HMGCR, APOB, and PCSK9

et al. 2022

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“…Peptide-based vaccines have so far shown promising results in mice or macaques, including the use of bacteriophage virus-like particles displaying PCSK9-derived peptides ( 204 , 205 ). Whether vaccination against PCSK9 using modified lipid nanoparticles ( 206 ) or effective capsid-like particles ( 207 ) expressing full-length PCSK9 will be approved to treat severe pathologies will have to be carefully evaluated for any harmful side effects of such an irreversible therapy ( 163 ).…”

Section: Future Strategies Beyond Mab and Sirnamentioning

confidence: 99%

The Multifaceted Biology of PCSK9

2021

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This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating LDL-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain (CHRD), its binding to the secreted cytosolic cyclase associated protein 1 (CAP-1), and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the anti-tumoral activity of CD8 + T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors (PCSK9i) that reduces by 50-60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 mAb or siRNA could be added to current immunotherapies in cancer/metastasis.

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“…Although vaccination is mainly used as a prophylactic strategy for infectious diseases, there is growing interest in the use of vaccines for preventing noninfectious diseases, such as cardiovascular disease. In mice, vaccines targeting PCSK9 were shown to markedly lower plasma LDL-C levels [ 37 ]. In response, a number of phase 1 human clinical trials with PCSK9 vaccine have been completed or initiated [ 38 ].…”

Section: Pharmacological Strategies For Angptl3 Inactivationmentioning

confidence: 99%

ANGPTL3 as therapeutic target

Kersten

2021

Current Opinion in Lipidology

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Purpose of review Elevated LDL-C and triglycerides are important risk factors for the development of atherosclerotic cardiovascular disease. Although effective therapies for lipid lowering exist, many people do not reach their treatment targets. In the last two decades, ANGPTL3 has emerged as a novel therapeutic target for lowering plasma LDL-C and triglycerides. Here, an overview of the recent literature on ANGPTL3 is provided, focusing on the therapeutic benefits of inactivation of ANGPTL3 via monoclonal antibodies, antisense oligonucleotides, and other more nascent approaches. In addition, the potential mechanisms by which ANGPTL3 inactivation lowers plasma LDL-C are discussed. Recent findings ANGPTL3 is a factor secreted by the liver that inhibits lipoprotein lipase and other lipases via the formation of a complex with the related protein ANGPTL8. Large-scale genetic studies in humans have shown that carriers of loss-of-function variants in ANGPTL3 have lower plasma LDL-C and triglyceride levels, and are at reduced risk of atherosclerotic cardiovascular disease. Clinical studies in patients with different forms of dyslipidemia have demonstrated that inactivation of ANGPTL3 using monoclonal antibodies or antisense oligonucleotides markedly lowers plasma LDL-C and triglyceride levels. Summary Anti-ANGPTL3 therapies hold considerable promise for reducing plasma LDL-C and triglycerides in selected patient groups.

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Vaccines Targeting PSCK9 for the Treatment of Hyperlipidemia

Cited by 14 publications

References 44 publications

Amino Acid Conjugates of 2-Mercaptobenzimidazole Ameliorates High-Fat Diet-Induced Hyperlipidemia in Rats via Attenuation of HMGCR, APOB, and PCSK9

Amino Acid Conjugates of 2-Mercaptobenzimidazole Ameliorates High-Fat Diet-Induced Hyperlipidemia in Rats via Attenuation of HMGCR, APOB, and PCSK9

The Multifaceted Biology of PCSK9

ANGPTL3 as therapeutic target

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