NEW CHOLESTEROL VACCINE: PIONEER OF HEART HEALTH
The low-density lipoprotein receptor (LDL-R), which is mostly expressed in the liver, eliminates LDL-C from the bloodstream. The complex is endocytosed once LDL-C and LDL-R connect. The complex dissociates due to the low pH of the endosome, which permits the cell to metabolize LDL-C and recycle LDL-R back to the plasma membrane for further removal of circulating LDL-C. A serum-associated secretory protein called proprotein convertase subtilisin/kexin type 9 (PCSK9) directly prevents LDL-R from being recycled. PCSK9 forms a strong binding with the extracellular domain of LDL-R, which facilitates its lysosomal breakdown after endocytosis.Thus, by inhibiting LDL-R recycling, PCSK9 mediates higher levels of circulating LDL-C.
Patients with gain of function (GOF) mutations have increased affinity of PCSK9 for LDL-R and can develop autosomal dominant hypercholesterolemia (ADH); these patients exhibit high levels of LDL-C and early onset ASCVD12. However,patients with loss of function (LOF) mutations in PCSK9 exhibit low LDL-C levels and a decreased risk of cardiovascular events
One method that shows promise for modifying PCSK9 activity is vaccination. Compared to other therapeutic techniques, vaccines have a number of potential benefits. For example, vaccines are generally cheap to make, which could lower expenses for patients, and they usually require fewer doses, which could improve patient compliance. The ability to elicit antibody responses against self-antigens, like PCSK9, is typically limited by immunological mechanisms of self-tolerance. However, these mechanisms can be effectively circumvented by displaying high densities of self-antigens on the surface of nanoparticle-based vaccine platforms, like virus-like particles (VLPs). Human clinical trials have assessed VLP-based vaccinations that target self-antigens, and the strategy has demonstrated safety and the ability to elicit high titer antibody responses. Recently developed VLP-based vaccinations showed various human PCSK9 linear peptides that were thought to interact with LDL-R.
It is discovered that a number of vaccine candidates that decreased total cholesterol levels in inoculated mice and produced high titer anti-PCSK9 antibody responses. In order to evaluate the effectiveness of these VLP-based vaccinations in inducing anti-PCSK9 antibody responses and lowering cholesterol in a variety of animal models, a design incorporating two species-specific linear peptides from PCSK9 into the vaccines was utilised. These results provide evidence in favor of using a bivalent VLP-based vaccine that targets two PCSK9 epitopes to efficiently reduce LDL-C levels without the need for statin co-administration.
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