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Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

ABSTRACT: BACKGROUND:Proprotein convertase subtilisin/kexin 9 (PCSK9) is an important regulator of low-density lipoprotein receptor (LDLR) and plasma levels of LDL cholesterol (LDL-C). PCSK9 inhibition is an efficient therapeutic approach for the treatment of dyslipidemia. We tested the therapeutic effect of a PCSK9 vaccine on dyslipidemia and atherosclerosis. METHODS:Lipid film hydration method was used to prepare negatively charged nanoliposomes as a vaccine delivery system. An immunogenic peptide called immunogenic fused PCSK9-tetanus (IFPT) was incorporated on the surface of nanoliposomes using DSPE-PEG-maleimide lipid (L-IFPT) and adsorbed to Alhydrogel® (L-IFPTA+). The prepared vaccine formulation (L-IFPTA+) and empty liposomes (negative control) were inoculated four times with bi-weekly intervals in C57BL/6 mice on the background of a severe atherogenic diet and poloxamer 407 (thrice weekly) injection. Antibody titers were evaluated 2 weeks after each vaccination and at the end of the study in vaccinated mice. Effects of anti-PCSK9 vaccination on plasma concentrations of PCSK9 and its interaction with LDLR were determined using ELISA. To evaluate the inflammatory response, interferon-gamma (IFN-?)- and interleukin (IL)-10-producing splenic cells were assayed using ELISpot analysis. RESULTS:L-IFPTA+ vaccine induced a high IgG antibody response against PCSK9 peptide in the vaccinated hypercholesterolemic mice. L-IFPTA+-induced antibodies specifically targeted PCSK9 and decreased its plasma consecration by up to 58.5% (-?164.7?±?9.6?ng/mL, p?= 0.0001) compared with the control. PCSK9-LDLR binding assay showed that generated antibodies could inhibit PCSK9-LDLR interaction. The L-IFPTA+ vaccine reduced total cholesterol, LDL-C, and VLDL-C by up to 44.7%, 51.7%, and 19.2%, respectively, after the fourth vaccination booster, compared with the control group at week 8. Long-term studies of vaccinated hypercholesterolemic mice revealed that the L-IFPTA+ vaccine was able to induce a long-lasting humoral immune response against PCSK9 peptide, which was paralleled by a significant decrease of LDL-C by up to 42% over 16?weeks post-prime immunization compared to control. Splenocytes isolated from the vaccinated group showed increased IL-10-producing cells and decreased IFN-?-producing cells when compared with control and naive mice, suggesting the immune safety of the vaccine. CONCLUSIONS:L-IFPTA+ vaccine could generate long-lasting, functional, and safe PCSK9-specific antibodies in C57BL/6 mice with severe atherosclerosis, which was accompanied by long-term therapeutic effect against hypercholesterolemia and atherosclerosis.

SUBMITTER: Momtazi-Borojeni AA

PROVIDER: S-EPMC6902459 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

Momtazi-Borojeni Amir Abbas AA Jaafari Mahmoud Reza MR Badiee Ali A Banach Maciej M Sahebkar Amirhossein A

BMC medicine 20191210 1

<h4>Background</h4>Proprotein convertase subtilisin/kexin 9 (PCSK9) is an important regulator of low-density lipoprotein receptor (LDLR) and plasma levels of LDL cholesterol (LDL-C). PCSK9 inhibition is an efficient therapeutic approach for the treatment of dyslipidemia. We tested the therapeutic effect of a PCSK9 vaccine on dyslipidemia and atherosclerosis.<h4>Methods</h4>Lipid film hydration method was used to prepare negatively charged nanoliposomes as a vaccine delivery system. An immunogeni ...[more]

PMID: 31818299

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Project description:BackgroundThe vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in melanoma development and progression. Peptide vaccines have shown great potential in cancer immunotherapy by targeting VEGFR-2 as a tumor-associated antigen and boosting the immune response against both tumor cells and tumor endothelial cells. Despite this, the low efficiency of peptide vaccines has resulted in moderate therapeutic results in the majority of studies. Enhancing the delivery of peptide vaccines using nanoliposomes is an important strategy for improving the efficacy of peptide vaccines. In this regard, we designed VEGFR-2-derived peptides restricted to both mouse MHC I and human HLA-A*02:01 using immunoinformatic tools and selected three peptides representing the highest binding affinities. The peptides were encapsulated in nanoliposomal formulations using the film method plus bath sonication and characterized for their colloidal properties.ResultsThe mean diameter of peptide-encapsulated liposomes was around 135 nm, zeta potential of - 17 mV, and encapsulation efficiency of approximately 70%. Then, vaccine formulations were injected subcutaneously in mice bearing B16F10-established melanoma tumors and their efficiency in triggering immunological, and anti-tumor responses was evaluated. Our results represented that one of our designed VEGFR-2 peptide nanoliposomal formulations (Lip-V1) substantially activated CD4+ (p < 0.0001) and CD8+ (P < 0.001) T cell responses and significantly boosted the production of IFN-γ (P < 0.0001) and IL-4 (P < 0.0001). Furthermore, this formulation led to a significant decrease in tumor volume (P < 0.0001) and enhanced survival (P < 0.05) in mice.ConclusionOur findings suggest that the nanoliposomal formulation containing VEGFR-2 peptides could be a promising therapeutic vaccination approach capable of eliciting strong antigen-specific immunologic and anti-tumor responses.Supplementary informationThe online version contains supplementary material available at 10.1186/s12645-023-00213-7.

Project description:Purpose of reviewSince the discovery of PCSK9 in 2003, this proprotein convertase was shown to target specific receptors for degradation in endosomes/lysosomes, including LDLR and other family members and hence to enhance the levels of circulating LDL-cholesterol (LDLc). Accordingly, inhibitors of PCSK9, including monoclonal antibodies blocking its circulating activity and siRNA silencers of its hepatic expression, are now used in clinics worldwide to treat hypercholesterolemia patients effectively and safely in combination with statins and/or ezetimibe. These powerful treatments reduce the incidence of atherosclerosis by at least 20%. Since 2008, novel targets of PCSK9 began to be defined, thereby expanding its roles beyond LDLc regulation into the realm of inflammation, pathogen infections and cellular proliferation in various cancers and associated metastases.Recent findingsSome pathogens such as dengue virus exploit the ability of PCSK9 to target the LDLR for degradation to enhance their ability to infect cells. Aside from increasing the degradation of the LDLR and its family members VLDLR, ApoER2 and LRP1, circulating PCSK9 also reduces the levels of other receptors such as CD36 (implicated in fatty acid uptake), oxidized LDLR receptor (that clears oxidized LDLc) as well as major histocompatibility class-I (MHC-I) receptors (implicated in the immune response to antigens). Thus, these novel targets provided links between PCSK9 and inflammation/atherosclerosis, viral infections and cancer/metastasis. The functional activities of PCSK9, accelerated the development of novel therapies to inhibit PCSK9 functions, including small molecular inhibitors, long-term vaccines, and possibly CRISPR-based silencing of hepatic expression of PCSK9. The future of inhibitors/silencers of PCSK9 function or expression looks bright, as these are expected to provide a modern armamentarium to treat various pathologies beyond hypercholesterolemia and its effects on atherosclerosis.

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Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

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Therapeutic effect of nanoliposomal PCSK9 vaccine in a mouse model of atherosclerosis.

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