Engineering chimeric PCSK9 for a vaccine against atherosclerosis
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ABSTRACT:
PROVIDER: PRJNA1188181 | ENA |
REPOSITORIES: ENA
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Project description:Cardiovascular diseases, especially atherosclerosis, are the major cause of death in the modern era. In most cases, amelioration is achieved by decreasing the concentration of LDL cholesterol in blood, using statins or monoclonal antibodies targeting PCSK9, which are highly efficient, but are costly and requires bimonthly administration. Vaccination against PCSK9 represents an attractive alternative with potentially long-lasting efficiency, but has to overcome the challenge of autoimmune reactivity against an endogenous protein to prevent healthy tissue damage. We developed an autologous chimeric vaccine against PCSK9, which triggers a B cell immune response to produce neutralizing antibodies but avoids induction of self antigen mediated T cell cytotoxicity. We demonstrated in atherosclerosis murine model that vaccination generated an adequate humoral immune response with the effect persistent over 24°weeks, observed in lower circulating PCSK9, lower cholesterol and reduced atherosclerotic disease burden in the aortas. This is a proof of concept study for a therapeutic amelioration of atherosclerosis, which also provides a perspective on the rational design of a vaccine against endogenous proteins.
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Project description:Atherosclerosis is an autoimmune disease characterized by lipid imbalances and chronic inflammation within blood vessels with limited preventive and treatment options currently available. Previous experiments have demonstrated the atheroprotective potential of collagen 6 subtype alpha6 (COL6A6) in apolipoprotein E-deficient (ApoE-/-) mice with hyperlipidemia. However, the mechanism underlying the anti-atherosclerotic effects of COL6A6 remains elusive. This knowledge gap was addressed in the present study by immunizing ApoE-/- mice with the Pep_A6 vaccine, comprising a COL6A6 peptide-KLH (keyhole limpet hemocyanin) conjugate and aluminum (Alum) hydroxide adjuvant, and conducting a series of experiments. Our objective was to investigate the efficacy of the Pep_A6 vaccine, focusing on immune responses and lipid metabolism. Our finding showed that the Pep_A6 vaccine represents a novel approach to combat atherosclerosis by inducing a large increase in Treg cells, the generation of antigen-specific antibodies and regulating lipid metabolism.
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Project description:We have transfected Hep2G cells with the gain-of-function mutant D374Y-PCSK9.
2008-01-30 | E-MEXP-1235 | biostudies-arrayexpress
Project description:Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived AQ3 from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (−38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake, whereas cells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (−89.7%; P<0.001) and had a 106% increase (P=0.0104) of LDL uptake. Pravastatin treatment significantly enhanced LDL receptor (LDLR) and PCSK9 mRNA gene expression, as well as PCSK9 secretion and LDL uptake in both control and S127R HLCs. Pravastatin treatment of multiple clones led to an average increase of LDL uptake of 2.19±0.77-fold in HLC-S127R compared to 1.38±0.49 fold in control HLCs (P<0.01), in line with the good response to statin treatment of individuals carrying the S127R mutation (mean LDL cholesterol reduction=60.4%, n=5). In conclusion, urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function.
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Project description:Mice lacking ADAM10 in endothelial cells (Tie2Cre driven) and flox-control mice were injected with an AAV8-PCSK9 virus and put on a Western-type diet for 10 weeks to induce atherosclerosis. Aorta's (Thoracoabdominal) were isolated (removal of PVAT) and processed for RNA-sequencing.
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Project description:Engineering A Potent Cancer Vaccine Using Immunoproteasome-Expressing Mesenchymal Stromal Cells
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Project description:In this study, mice with different genotypes and fed diets with different lipid content were enrolled, aiming to set up an atlas of miRNA expression levels in different organs with a relevant role in lipid/lipoprotein metabolism. Specifically, three genotypes were investigated: C57Bl/6 mice as controls, together with mice knock-out (KO) for LDLr (low-density lipoprotein receptor) and for PCSK9 (proprotein convertase subtilisin/kexin type 9). LDLr and PCSK9 are both involved in LDL turnover, the former mediating LDL clearance [PMID: 19299327], the latter causing the degradation of the LDLr protein [PMID: 17080197]. As a result, LDLrKO mice, because of their impaired LDL catabolism, are hypercholesterolemic and prone to atherosclerosis development, particularly when fed high-fat, cholesterol-containing diets [PMID: 8349823; PMID: 8182121]. On the contrary, PCSK9KO mice, characterized by an accelerated LDL catabolism, are hypocholesterolemic and atherosclerosis resistant [PMID: 15805190]. miRNA expression was investigated in liver, intestine, aorta, white adipose tissue and brain of mice on both standard and Western diet.
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