Table 3 PCSK9 vaccine and inhibitors

Statin

This way, PCSK9 polymorphisms were used as stand-ins for statin treatment. For each unit change in LDL-C, the mutations in both sites had similar effects on the risk of ASCVD when added together or on their own. According to the results of this study, blocking PCSK9 may lower the chance of heart disease by the same amount per change in LDL-C as statin treatment. The benefits may be separate or add up.

[82]

Anti-sense

It stops the PCSK9 gene from being expressed by attaching to its messenger RNA (mRNA) precursor. This leads to an increase in hepatocyte recycling and LDLR expression on the cell surface while LDL-c levels decrease.

[67]

mAb

The fact that mAbs can avoid the liver and kidneys’ metabolic processes, which lowers drug interactions, and that they can specifically bind to targets of interest through the antigen binding site, which makes these targets ineffective and reduces off-site effects, are both good things about them. So, improvements in antibody technology made it seem like a good idea to stop PCSK9 with mAbs that are 100% human.

[68, 69]

P-21

By employing high-throughput optimization techniques and conducting a series of assessments, it was possible to synthesize and characterize a stable water-dispersible nano-encapsulated drug (named P-4) conjugated with a hepatic targeting moiety (named P-21). P-21 presents a practicable and more efficient treatment protocol in contrast to the FDA-approved mAbs that target uncontrolled hypercholesterolemia to mitigate the risk of CVDs.

[71]

Alirocumab and Evolocumab

Currently the most efficacious cholesterol-lowering compounds on the market, these mAbs reduce the risk of atherosclerotic CVD and diminish LDL-C levels by up to 73%. Novel PCSK9 inhibitors have been developed via genome editing technology (CRISPR-Cas9), antisense oligonucleotide silencing agents (siRNA), vaccines, mimetic peptides, adnectins, and PCSK9 secretion inhibitors as a result of ongoing research.

[72]

MK-0616

The result was a macrocyclic peptide (MK-0616) that exhibited exceptional selectivity and potency towards PCSK9. With a high affinity (Ki = 5 pM) for PCSK9 as observed in vitro, MK-0616 demonstrated adequate safety and oral bioavailability in preclinical studies, facilitating its progression to the clinic. Similarly, after 14 days of once-daily dosing of 20 mg MK-0616, multiple oral-dose regimens offered participants on statin therapy the highest possible reduction of 61% geometric mean (95% CI: 43–85) in LDL-C from baseline.

[73]

ANGPTL3

Particularly, gene-editing treatments and vaccines have the potential to reduce PCSK9 or ANGPTL3 activity over an extended period significantly or to knock it down with a single treatment completely. Biologic treatments that are modeled after situations of monogenic hypocholesterolemia are becoming useful in preventing atherosclerotic CVDs

[75]

rHSP25

rHSP25 vaccination is correlated with reduced cholesterol levels and atherogenesis after OVX, a process accompanied by an increase in LDLR expression but not PCSK9 expression.

[76]

Anti-PCSK9 vaccines based on peptides

Anti-PCSK9 vaccines based on peptides elicit the production of antibodies that retain their functionality, affinity, and persistence for one year. As potent and risk-free instruments for long-term LDL-C management, they may represent a novel therapeutic strategy for the prevention and/or treatment of CVDs associated with LDL hypercholesterolemia in humans.

[77]

L-IFPTA + vaccine

The L-IFPTA + vaccine induced a long-lasting humoral immune response against PCSK9 peptide in vaccinated hypercholesterolemic mice, according to long-term studies. This response was accompanied by a significant reduction in LDL-C by up to 42% over 16 weeks after primary immunization, relative to the control group. Splenocytes obtained from the vaccinated group exhibited a more significantly proliferation of IL-10-producing cells and a reduction in IFN-γ-producing cells compared to the control and naive mouse groups.

[83]

L-IFPTA

The L-IFPTA vaccination can suppress PCSK9-specific T-cell activation while stimulating a tetanus-specific T-cell response that amplifies PCSK9-specific B-cell activation, all without causing any safety issues. This leads to producing memory and plasma B cells, which can consistently generate high-titer antibody responses. However, clinical data about L-IFPTA remain insufficient until further measures are implemented.

[78]

VLP-based vaccines

Vaccinated with bacteriophage VLPs containing PCSK9-derived peptides, mice and macaques produced IgG antibodies with a high titer bound to circulating PCSK9. Significant reductions in total cholesterol, free cholesterol, phospholipids, and TGs were observed in individuals who received vaccinations. Therefore, PCSK9-targeting vaccines may be a viable alternative to mAb-based therapies.

[79]

VLP-based vaccines

A VLP vaccine that specifically targeted a PCSK9 epitope demonstrated efficacy in reducing LDL-C levels in macaques only when administered in conjunction with statins. Conversely, immunization with the bivalent vaccine reduced LDL-C levels independently of the need for statin co-administration. The effectiveness of an alternative, vaccine-based strategy for reducing LDL-C is highlighted by these results.

[84]

FL PCSK9 cVLP vaccine

The results of this head-to-head immunization study demonstrate that the FL PCSK9 cVLP vaccine possesses a substantially enhanced ability to opsonize and eliminate plasma PCSK9.

[80]

ABEs

Researchers aimed to assess the effectiveness and safety of ABEs in reducing blood LDL levels in the livers of cynomolgus macaques and mice. Re-dosing did not enhance editing in macaques, possibly due to the humoral immune response to ABE detected upon treatment.

[81]