PCSK9

• OMIM: 607 786
• UniProt: Q8NBP7
• MGI: 2140260

The proprotein convertase subtilisin / kexin type 9 (English proprotein convertase subtilisin / kexin type 9, in short: PCSK9; neural apoptosis -regulated convertase -1, NARC -1) is a serine protease. This enzyme is involved in fat metabolism.

Properties

Proprotein convertases activate inactive precursor forms of proteins ( the proprotein ) by removing a prosegment and so the active protein (eg, hormone receptor) release. There have been characterized up to now nine proprotein, including most recently PCSK9. PCSK9 is of clinical importance because it reduces the number of LDL - receptors at the cell membrane of the liver cells and thus the concentration of LDL cholesterol in the blood. Mutations of the PCSK9 gene are the third most common cause of hypercholesterolemia (ADH ) in patients with homozygous autosomal dominant hypercholesterolemia dar.

The development of PCSK9 inhibitors is an approach for the treatment of severe LDL Hypercholesterininämien.

Function

PCSK9 is located predominantly in the liver. The inactive PCSK9 undergoes autocatalytic cleavage at the endoplasmic reticulum, before it is then secreted from liver cells into the circulation. The cleaved prosegment remains associated with the active protein at its catalytic center. This could explain why no catalytic activity of PCSK9 is known except this self-cleavage.

The effects of PCSK9 on LDL receptor and LDL - cholesterol levels are independent of its catalytic function, but effected by binding to the LDL receptor, and thereby the enhanced degradation. Of therapeutic interest is the effect of PCSK9 on the reduction of LDL - receptors, which remove the LDL cholesterol from the bloodstream. Circulating LDL cholesterol is degraded mainly by the LDL receptor in the liver. LDL receptors bind circulating LDL cholesterol and are funneled together by endocytosis into the cell. Due to the drop in pH in the endosomes to LDL - cholesterol and LDL - receptor disconnect. While LDL cholesterol is metabolized in the liver cell further, the receptors are again transported to the cell surface for receiving another LDL cholesterol.

PCSK9 regulates the LDL cholesterol levels by binding to the LDL receptor and is taken up with him by the liver cell. PCSK9 bound LDL receptors are degraded in this case and not be transported again to the cell surface and thus no longer available for LDL binding available. Thus, the LDL cholesterol level in plasma increases.

Hypercholesterolaemia

Independent risk cofactors for coronary heart disease LDL - cholesterol and lipoprotein (a) elevation and degraded HDL. The exposure time is critical, so that genetic forms of hypercholesterolemia for the development of atherosclerosis are particularly significant.

In milder forms of dyslipidemia treatment in the form of lifestyle measures carried out. With increased total cardiovascular risk and the failure to achieve target LDL value by lifestyle measures usually a statin therapy is indicated. In patients with a particularly high risk should, according to guidelines should be an LDL cholesterol level less than 70 mg / dl should be sought. In patients with proven atherosclerosis even in LDL from baseline of less than 100 mg / dl, the use of a statin is useful. These target values ​​are difficult to achieve for many patients with familial hypercholesterolemia despite medical therapy.

Genetics

Familial hypercholesterolemia is an autosomal dominant disease characterized by increased plasmatic LDL levels, xanthomas, and early coronary artery disease. The causes mutations have been so far discovered three genes that affect all three of the function of the LDL receptor: mutations of the LDL receptor gene, the apoB100 gene and the PCSK9 gene.

In 2003, families were discovered with familial hypercholesterolemia mutations of a newly identified gene in two French, the PCSK9 gene on chromosome 1 ( Nat Genet Abifadel 2009). This turned out to be gain -of-function mutations. Since then, many other mutations of the PCSK9 gene, inter alia, loss-of- function mutations in patients with low LDL - cholesterol and low CHD risk were found. Gain - of-function mutations are rare mutations and occur in third place of the causes of the homozygous ADH, far short of the LDL receptor and apoB mutations. In the meantime, however, more than 100 of the PCSK9 gene variants have been identified, which might be responsible for a large portion of the heavy hypercholesterolemia.

Regulation

PCSK9 and LDL receptors are both regulated mainly by the intracellular cholesterol levels: decreases of these mirrors, a gene expression of LDL receptor and PCSK9 is induced. The mechanism of action of statins is the inhibition of a key enzyme (HMG -CoA reductase, SREBP ), and leads to a reduction in intracellular cholesterol, the liver cell. They are therefore also known as HMG -CoA reductase inhibitors. The effect on the SREBP leads regulative to an increase in production ( and secretion ) of PCSK9, ie statins increase PCSK9 levels and thus attenuate somewhat their actual LDL reduction potential. This may explain why statins with an LDL cholesterol reduction of more than 50 % is hard to achieve. From a combination of statins with PCSK9 inhibitors is promised to an additive effect.

Drug Targeting

Among the new therapeutic approaches to the reduction in LDL cholesterol form, in addition to MTP inhibitors (eg Lomitapid ) and antisense oligonucleotides against apoB (eg Mipomersen ) that PCSK9 inhibitors is a particularly active area of ​​research. The discovery of the PCSK9 gene and its mutations is an example of genetics controlled therapy development.

The development of monoclonal anti- PCSK9 antibody is most advanced. These monoclonal antibodies will bind to the circulating PCSK9 and prevent their binding to the LDL receptors. The reduction of LDL - cholesterol via the LDL receptors is increased. It run some phase III studies ( pivotal studies ):

• Alirocumab ( SAR236553/REGN727 ) is being developed by Sanofi and Regeneron. A program is already running with 12 parallel Phase III studies ( ODYSSEY program), are examined in total 23,000 patients.
• Evolocumab ( AMG145 ) is being developed by Amgen. As part of the pRoFicio phase III program 20 Phase III studies are planned with the inclusion of 30,000 patients.
• The company Pfizer has begun Bococizumab (No. 316 ) with the phase II studies.

Other approaches for PCSK9 inhibitors have been far less successful ( small molecules, peptide mimetics, gene silencing ).