A cholesterol-lowering VLP vaccine that targets PCSK9

Crossey, Erin; Amar, Marcelo; Sampson, Maureen; Peabody, Julianne; Schiller, John T.; Chackerian, Bryce; Remaley, Alan T.

doi:10.1016/j.vaccine.2015.09.044

Cited by 126 publications

(128 citation statements)

References 45 publications

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“…For example, in the transethnic meta-analysis we observed three independent signals in PCSK9 systematically associated with lower LDL-C across multiple race/ethnicities; this suggests that the knockdown of PCSK9 should also lower LDL-C across ethnicities (16). In fact, clinical studies are already underway to for PCSK9 as a potential drug target for LDL-C reduction (17). Our results suggest such drugs could be efficacious across multiple ancestral populations.…”

Section: Discussionmentioning

confidence: 57%

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Zubair

Graff²,

Ambite

et al. 2016

Human Molecular Genetics

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Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.

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Section: Discussionmentioning

confidence: 57%

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Zubair

Graff²,

Ambite

et al. 2016

Human Molecular Genetics

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“…Specifically, lipidoid nanoparticles achieving liver-specific RNAi silencing of PCSK9 (60) are currently in phase II and have a potential for bi-annual dosing (Alnylam Pharmaceuticals). PCSK9 vaccines, peptide-or virus-like particle-based, were also developed and achieved ϳ50% lower total and/or LDLc levels for up to 1 year in rodents and/or primates (61,62).…”

Section: Figure 8 In Vivo Efficacy Of the Sdab P140 After Two Injecmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation

Weider

Susan‐Resiga

Essalmani

et al. 2016

Journal of Biological Chemistry

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Single domain antibodies (sdAbs) correspond to the antigenbinding domains of camelid antibodies. They have the same antigen-binding properties and specificity as monoclonal antibodies (mAbs) but are easier and cheaper to produce. We report here the development of sdAbs targeting human PCSK9 (proprotein convertase subtilisin/kexin type 9) as an alternative to anti-PCSK9 mAbs. After immunizing a llama with human PCSK9, we selected four sdAbs that bind PCSK9 with a high affinity and produced them as fusion proteins with a mouse Fc. All four sdAb-Fcs recognize the C-terminal Cys-His-rich domain of PCSK9. We performed multiple cellular assays and demonstrated that the selected sdAbs efficiently blocked PCSK9-mediated low density lipoprotein receptor (LDLR) degradation in cell lines, in human hepatocytes, and in mouse primary hepatocytes. We further showed that the sdAb-Fcs do not affect binding of PCSK9 to the LDLR but rather block its induced cellular LDLR degradation. Pcsk9 knock-out mice expressing a human bacterial artificial chromosome (BAC) transgene were generated, resulting in plasma levels of ϳ300 ng/ml human PCSK9. Mice were singly or doubly injected with the best sdAb-Fc and analyzed at day 4 or 11, respectively. After 4 days, mice exhibited a 32 and 44% decrease in the levels of total cholesterol and apolipoprotein B and ϳ1.8-fold higher liver LDLR protein levels. At 11 days, the equivalent values were 24 and 46% and ϳ2.3-fold higher LDLR proteins. These data constitute a proof-of-principle for the future usage of sdAbs as PCSK9-targeting drugs that can efficiently reduce LDL-cholesterol, and as tools to study the Cys-His-rich domain-dependent sorting the PCSK9-LDLR complex to lysosomes.For over 30 years, a large number of clinical trials have firmly consolidated the importance of lowering LDL-cholesterol (LDLc) 3 in the prevention of cardiovascular diseases (CVD) and its associated devastating sequelae (1). Healthy diets and exercise are highly recommended to lower LDLc in patients with high baseline levels. However, many individuals, including those suffering from familial hypercholesterolemia (FH), cannot reach the recommended LDLc levels to prevent cardiovascular complications. With an overall incidence of ϳ1:200, FH is a common inherited disease that affects at least 30 million people, of whom Յ1% have been diagnosed. It is characterized by plasma LDLc levels greater that the 95th percentile, which result in tendon xanthomas, xanthelasmas, corneal arcus, and premature atherosclerosis, leading to premature ischemic vascular disease and mortality if left untreated. In most cases, FH subjects exhibit mutations in the LDL receptor (LDLR; 67%) and its ligand apolipoprotein B (apoB; 14%), hampering LDL clearance from the circulation (2). In 2003, merging biological studies with human genetics led to the discovery of PCSK9, the 9th and last member of the family of proprotein convertases related to subtilisin and kexin (3), and the demonstration that the PCSK9 gene represents the 3rd locus of autosomal domin...

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“…Thus investigators have been testing the notion of active immunization against PCSK9 to achieve similar but long-term biological effects to the use of PCSK9 antibody. In preclinical experiments, PCSK9 peptide-based vaccines have been shown to elicit a PCSK9-specific antibody with a significant reduction of LDL-C. 68,69 If these vaccines can be further demonstrated to be well tolerated and effective for clinical application, active immunization against PCSK9 will be an attractive alternative to the PCSK9 antibody.…”

Section: Pcsk9 Vaccinesmentioning

confidence: 99%

Vaccine against arteriosclerosis: an update

Chyu

Dimayuga

Shah

2017

Therapeutic Advances in Vaccines

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Substantial data from experimental and clinical investigation support the role of immune-mediated mechanisms in atherogenesis, with immune systems responding to many endogenous and exogenous antigens that play either proatherogenic or atheroprotective roles. An active immunization strategy against many of these antigens could potentially alter the natural history of atherosclerosis. This review mainly focuses on the important studies on the search for antigens that have been tested in vaccine formulations to reduce atherosclerosis in preclinical models. It will also address the opportunities and challenges associated with potential clinical application of this novel therapeutic paradigm.

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A cholesterol-lowering VLP vaccine that targets PCSK9

Cited by 126 publications

References 45 publications

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Single Domain Antibodies Are Potent Inhibitors of Low Density Lipoprotein Receptor Degradation

Vaccine against arteriosclerosis: an update

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