PCSK9, a Review of the Progress from Discovery to Therapy

PCSK9 inhibition therapies dramatically reduce cholesterol levels in the bloodstream, and seem set to take over from statins as the next generation approach to cholesterol management in the context of cardiovascular disease risk. Atherosclerosis results from the ability of a combination of damaged lipids - such as oxidized cholesterol - and overall level of lipids to overwhelm macrophage cells called in to clean up points of irritation in blood vessel walls. A feedback loop of inflammation and cell death sets in, as macrophages, filled with lipids and in the process of dying, call for further help, secreting cytokines that produce inflammation. The fatty deposits that weaken and narrow blood vessels in the later stages of atherosclerosis are composed of dead macrophages and the lipids they failed to clean up.

One way to try to slow down this runaway process of damage is to reduce the input of cholesterol. This is the basis of the success of statins in lowering cardiovascular risk, and the evidence suggests that further lowering of cholesterol levels will reduce that risk to a greater degree. This is still, however, only a stepping stone on the way to an effective and complete solution. PCSK9 inhibition doesn't halt or significantly reverse atherosclerosis, it still only slows it down somewhat. The research community must focus on different mechanisms and strategies, such as perhaps ways to make macrophages more resilient and more effective, allowing them to continue to operate in old people just as well as they do in young people. The SENS approach of removing oxidized lipids via delivery of bacterial enzymes is one example.

Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery.

Initial clues were provided by a French family with familial hypercholesterolemia (FH) in 2003. Gain-of-function mutations in PCSK9 were linked with hypercholesterolemia and ultimately uncovered a key new player in lipid metabolism. This seminal discovery led to a series of investigations that demonstrated that loss-of-function (LOF) mutations in PCSK9 associate with lifelong low cholesterol levels and marked reductions in the risk of atherosclerotic cardiovascular disease (ASCVD). The rare individuals with homozygous LOF mutations in PCSK9 (and no circulating protein) demonstrated extremely LDL cholesterol (LDL-C; ≈15 mg/dL), normal health and reproductive capacity, and no evidence of neurological or cognitive dysfunction.

This complementary set of observations has been leveraged into the most important therapy for the treatment of hypercholesterolemia and ASCVD since the introduction of statins. Indeed, the so-called PCSK9 inhibitors, fully human monoclonal antibodies that bind PCSK9, reduce LDL-C by ≈60% and risk of myocardial infarction and stroke by ≈20% after more than 2 years of treatment. Remarkably, these agents antagonizing PCSK9 action were approved by regulatory agencies spanning the globe only a decade after its discovery - although the scientific and medical communities have swiftly uncovered many facets of PCSK9 biology, there is still much to learn.

Link: https://doi.org/10.1161/CIRCRESAHA.118.311227

Comments

I had a vivid dream that a heart surgeon was rubbing some viscous liquid into the veins and arteries around a heart. He made an incision into one of the larger arteries and pulled out the plaque in one piece, like the arteries and veins were an exterior mold. Is their a bio-safe solvent that could liquefy the boundary between the plaque and artery/vein wall?

Posted by: Tom Schaefer at May 21st, 2018 7:44 AM

From Vince Blog
"increased expression of the PCSK9 gene is due in part to the Insulin/IGF-1 signaling pathway, which prevents FoxO3a transcription factor from migrating into the cell nucleus, the most cost effective way to reduce PCSK9 expression is to reduce your insulin levels
fasting has been scientifically shown to be the cheapest and most effective way to reduce PCSK9. With a 48-hour fast, PCSK9 levels can be lowered by 58%, which is even more than the monoclonal antibodies do!"

Posted by: Salman at May 21st, 2018 10:30 AM

on an unrelated note, Unity biotech started their first clinical trial

Posted by: Chria at May 21st, 2018 12:29 PM

2 Salman
Something don't add up here. Cholesterol levels are actually increasing during fasts.
Its also not that clear cut whether lowering cholesterol is actually beneficial. Optimal TC levels for all-cause mortality are much higher than recommended by cardiologists. If I recall correctly cholesterol as a prognostic marker has some utility only for middle age men, women and elderly(regardless of gender) are actually better off with high TC.
To me, all this battle with cholesterol is useless, better fight causes of inflammation instead.

Posted by: Andey at May 21st, 2018 1:04 PM

Hi Salman,
Fasting when done correctly has many benefits but is hard to practise within the modern lifestyle. And Unfortunately we don't see scores of super centarian hermits. Probably fasting can extend the health span , bring some impressive cures here and there but will not itself alone allow you to live to 150 years.
I myself do some irregular fasting
Last month I did a 4 days fats. For a few days I felt a few years younger then the effects wasted off. I did 2 days late week. The effects are much weather than 4 days. But at least my BMI is going down...

Posted by: Cuberat at May 21st, 2018 3:04 PM

@Chria
Can you give more details or a link?

Posted by: Cuberat at May 21st, 2018 3:06 PM

@Andey
Isn't LDL cholesterol pro -inflammatory?

Posted by: Cuberat at May 21st, 2018 3:08 PM

Hi, just a 2 cent.

This study should be taken with precaution (I suffer from ischemic atherosclerosis, anginas and now global ischemia thanks to that since there is lasting DNA epigenetic clock trace memory from these traumatic events where you go into shock and tremble just like heart attack (impending death doom feel) and arterial clot/plaque ischemic destruction)). I suffer all these events and still alive, just as in the article I am suffering of deleterious French hypercholesteremia mutation (Biological French-Canadian Colonial Caucasian gene variant traced to France)..And I'm very thin (130lbs, 5'10).

One study showed deleterious effects from PCSK9 inhibition, basically reducing LDL is what saved my life but more specifically it was not reducing LDL alone; but swapping LDL species production for HDL production instead.
Atherosclerosis is determined by HDL:LDL ratio, low HDL to LDL equals not only Atherosclerosis progression but all-cause mortality increase and thus, sudden death. HDL is protective and genetically signals macrophage reprogramming towards reduced invasion and thus, inflammation/LDL fatty plaque formation in arterial lesions (LDL macrophage uptake reduced) and macrophage inflammation ROS redction since they senesce producing SASP/p53/TNF/thrombin and fibrosis))..
You need cholesterol but in a precise HDL:LDL ratio, the higher this ratio the best and is inversely correlated and causated to all-cause mortality and sudden death. Lowering LDL AND HDL at the same time is deadly. The only solution is liver production of HDL instead of LDL, thus liver enzyme HDL production (enzymatic competition between LDL and HDL production enzymes, needing to switch (to HDL specie competition win over LDL specie, the LDL levels drop dramatically after that (vitamin D3, homocysteine and methyl donors control LDL HDL cascade via liver stearoyl receptor-X))

New Cholesterol Drug PCSK9 [inhibitor] Is Likely To Prematurely Kill You
1. https://articles.mercola.com/sites/articles/archive/2013/07/29/pcsk9-cholesterol-drug.aspx

Posted by: CANanonymity at May 21st, 2018 4:10 PM

I am genetically blessed with a high HDL level of around 85. My LDL level varies from 105 to 115, but since my ratio is so good, I have rejected going on statins, even though my Doctor recommended it.

Posted by: Biotechy at May 22nd, 2018 7:37 AM

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