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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-γ)- 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-γ-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]

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