If PCSK9 is blocked, the LDL-LDLR complex separates during trafficking, with the LDL digested in the lysosome, but the LDLRs instead recycled back to the cell surface and so able to remove additional LDL-particles from the extracellular fluid.

[18] In February 2003, Nabil Seidah and Jae Byun, a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human proprotein convertase, the gene for which was located on the short arm of chromosome 1.

[19] Meanwhile, Helen H. Hobbs and Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples.

[22] With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found nonsense mutations in the gene, thus validating PCSK9 as a biological target for drug discovery.

[36] As a negative post-translational regulator of the low-density lipoprotein receptor (LDLR), PCSK9 plays a major role in cholesterol homeostasis.

[40] This conformational change in turn induces the dissociation of the LDL-LDLR complex, allowing LDLR to be recycled back to the plasma membrane.

[40] Thus, PCSK9 lowers cell surface expression of LDLR and thereby decreases metabolism of LDL-particles, which in turn may lead to hypercholesterolemia.

[41] PCSK9 also plays an important role in triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.

[50][21][51] The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.

[53] Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis.

[57] As PCSK9 binds to LDLR, which prevents the removal of LDL-particles from the blood plasma, several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).

[57][64][65] In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity,[66] regulation of re-absorption of sodium in the kidney which is relevant in hypertension.

[72] A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy.

A meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.

[82] The most recent guidelines for cholesterol management from the American Heart Association and American College of Cardiology now provide guidance for when PCSK9 inhibitors should be considered, particularly focusing on cases in which maximally tolerated statin and ezetimibe fail to achieve goal LDL reduction.

Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.

[90] The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice.

[92][93] Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.

[78][94][95] In 2021, scientists demonstrated that CRISPR gene editing can decrease blood levels of LDL cholesterol in vivo in Macaca fascicularis monkeys for months by 60% via knockdown of PCSK9 in the liver.

VLPs consist of the outer shell of a virus particle but lack a viral genome and are unable to replicate; they can induce immune responses without causing infection.

Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9.

[100] The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro,[101] and lowers serum PCSK9 in mice and hamsters in vivo.