What are Cholesterol Vaccines?

Published

2 years ago

July 25, 2023

admin

By Syed S. A. Reviewed by Sophia Coveney

Low-density lipoproteins (LDLs)
PCSK9 gene
Therapeutic strategies
Inclisiran
References
Further reading

High levels of low-density lipoprotein (LDL) cholesterol can cause artery blockages and diseases like heart attacks and strokes. Further, it raises the risk of cardiovascular disease (CVD). Thickened arteries and veins with cholesterol. Image Credit: NPW-STUDIO/Shutterstock.com

Although medicine and lifestyle modifications can considerably lower LDL, a considerable portion of at-risk individuals who are receiving therapy nevertheless experience a cardiovascular event.

Vaccines targeting proprotein convertase subtilisin/kexin 9 (PCSK9), an important regulator of LDL receptors, can be highly beneficial. Low-density lipoproteins (LDLs)

There are five main forms of lipoprotein that transport cholesterol in the body's aqueous extracellular environment. The primary organ for the metabolism of cholesterol and control of plasma cholesterol levels is the liver.

When the liver repackages intrahepatic cholesterol into very low-density lipoprotein (VLDL), either through de novo synthesis or gut absorption, the process of LDL production starts.

Once in the bloodstream, VLDL is changed into more cholesterol-rich species, intermediate-density lipoprotein (IDL), and ultimately LDL, by the enzymes lipoprotein lipase and cholesteryl ester transfer protein (CETP). By clearing them through LDL receptors on the hepatic surface, the liver predominantly controls the quantity of these circulating lipoprotein types.

LDL receptors (LDL-R), highly expressed in hepatocytes, interact with LDL in plasma to remove it from circulation. LDL is endocytosed and undergoes lysosomal degradation as a result of LDL-R binding. LDL-R is then recycled back to the cell surface after this procedure.

Circulating LDL particles can pass through the endothelium of artery walls, where they can oxidize, cause inflammation, and damage the adjacent smooth muscle cells and overlaying endothelium. PCSK9 gene

PCSK gene forms a protein that helps control the quantity of cholesterol in the bloodstream. The body produces cholesterol, a waxy, fatty molecule, and it can also be consumed through foods that contain animals.

The quantity of low-density lipoprotein receptors, which are proteins on the surface of cells, is regulated by the PCSK9 protein. These receptors are essential for controlling the amount of cholesterol in the circulation.

Low-density lipoproteins (LDLs), the main transporters of cholesterol in the blood, attach to the receptors. The liver, which removes the majority of extra cholesterol from the body, contains a lot of low-density lipoprotein receptors.

The rate at which cholesterol is eliminated from the bloodstream depends on the quantity of low-density lipoprotein receptors on the surface of liver cells. More cholesterol can stay in the bloodstream because the PCSK9 protein destroys low-density lipoprotein receptors before they reach the cell surface. Cholesterol testing. Image Credit: megaflopp/Shutterstock.com Therapeutic strategies

The finding that the LDL receptor is encouraged to degrade by the PCSK9 opened up a new method for regulating plasma LDL cholesterol levels. Monoclonal antibodies were the mainstay of the initial therapeutic strategies to lower PCSK9 levels in circulation. Related StoriesSelection bias in women's health studies may mask earlier onset menopause for Black and Hispanic womenHow does your Skin Change during Menopause?Endocrine Society's new Scientific Statement focuses on endocrine-related changes and aging

Alirocumab, evolocumab, and inclisiran are three pharmaceuticals that can lower PCSK9 activity and are offered in the US. Fully humanized monoclonal antibodies that are injected subcutaneously every 2 to 4 weeks, alirocumab and evolocumab, are very effective at reducing both total and LDL cholesterol.

They typically lower LDL cholesterol levels by 50% to 60%, whether used as monotherapy or in conjunction with a statin. As long as the treatment is given, the effect lasts.

FDA-approved bempedoic acid, a non-statin medication, lowers LDLc by blocking ATP citrate lyase, a crucial enzyme in the process that produces cholesterol. It is administered to patients in the US who have established atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia.

Another oral chemical, gemcabene calcium, has been tested in rat experiments for its lipid-lowering actions that are not dependent on PPARs (peroxisome proliferator-activated receptor alpha). In male rats, this chemical reduced LDLc, TG, and apolipoprotein C-III levels. It is currently being researched. Inclisiran

A small interfering RNA (siRNA) called inclisiran prevents PCSK9 from being synthesized inside cells. When given to people taking the highest dosage of a statin, inclisiran cuts LDL cholesterol by 50%.

In one study, two doses of 284 mg of inclisiran, or 300 mg of inclisiran sodium, given on days 1 and 90, resulted in a 52.6% reduction in LDL cholesterol at 180 days.

Data from the same trial followed the same patients for 360 days. It was revealed that inclisiran might offer long-lasting reductions in LDL cholesterol levels, with the possibility of a once-every-six-month treatment regimen.

In another study, patients with atherosclerotic cardiovascular disease (ORION-10 trial) and those with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent were enrolled in a trial. Patients were also enrolled in the ORION-10 trial. Even though they were taking statin medication at the maximum tolerable dose, their LDL cholesterol levels were increased. A subcutaneous injection of inclisiran (284 mg) or a placebo was given to patients randomly in a 1:1 ratio on day 1, day 90, and then every six months for a total of 540 days.

There were two coprimary endpoints in each trial. First was the placebo-corrected percentage change in LDL cholesterol level from baseline to 510th day. Second was the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.

Although injection-site adverse events were more frequent with inclisiran than with placebo, the reactions were typically mild, and none were severe or persistent. Overall, adverse events were comparable between the inclisiran and placebo groups in each trial.

With inclisiran, given subcutaneously every six months, LDL cholesterol levels were reduced by about 50%. According to the investigation, inclisiran can be dosed sparingly to achieve long-lasting drops in LDL cholesterol levels.

Further understanding of the LDL mechanism and the trial of different therapeutic agents in patients can add to the existing therapy. References Pokhrel B, Yuet WC, Levine SN (2023). PCSK9 Inhibitors. [Updated 2022 May 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448100/ Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP. (2020). ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Crismaru I, Pantea Stoian A, Bratu OG, Gaman MA, Stanescu AMA, Bacalbasa N, Diaconu CC (2020). Low-density lipoprotein cholesterol lowering treatment: the current approach. Lipids Health Dis. May 6;19(1):85. doi: 10.1186/s12944-020-01275-x. Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P, Wright RS, Kastelein JJ (2017). Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. Apr 13;376(15):1430-1440. doi: 10.1056/NEJMoa1615758. Pan Y, Zhou Y, Wu H, Chen X, Hu X, Zhang H, Zhou Z, Qiu Z, Liao Y. (2017). A Therapeutic Peptide Vaccine Against PCSK9. Sci Rep. Oct 2;7(1):12534. doi: 10.1038/s41598-017-13069-w. Wadhera RK, Steen DL, Khan I, Giugliano RP, Foody JM (2016). A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. May-Jun;10(3):472-89. doi: 10.1016/j.jacl.2015.11.010. Crossey E, Amar MJA, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT (2015). A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. Oct 26;33(43):5747-5755. doi: 10.1016/j.vaccine.2015.09.044. PCSK9 gene. [Online]. Medline Plus. Available at: https://medlineplus.gov/genetics/gene/pcsk9/

Further ReadingAll Vaccine ContentWhat are Vaccines?Vaccine HistoryWhat is a Vaccine Breakthrough?What are the Main Causes of Vaccine Hesitancy?More…

Last Updated: Jul 24, 2023

Politics

Victims’ families criticise ‘deeply sensitive decision’ to demolish Grenfell Tower

Published

1 hour ago

February 6, 2025

admin

Grenfell Tower to be demolished, as campaigners react to 'divisive and painful debate' over decaying block

Grenfell campaigners have reacted to the “deeply sensitive decision” by the deputy prime minister to demolish the tower block.

Victims’ families and survivors were given the news in a meeting attended by Angela Rayner on Wednesday night.

Grenfell Next of Kin, which represents some of the bereaved families, described it as a “deeply sensitive decision… after a thorough engagement process in person” following an “uncomfortable conversation with uncomfortable truths”.

In a statement on X the group said: “The lack of closure, the continuous discussions and consultations, the retraumatisation of a divisive and painful debate brings nothing to the table except pain and further division.

“We want a discussion about what will go in the Tower’s place so it can be seen and remembered forever. We need to re-imagine a future and rebuild our broken shattered lives and our families.”

The government has previously said there will be no changes to the site before the eighth anniversary of the fire disaster, which claimed 72 lives on 14 June 2017.

It is expected more details will be set out by ministers by the end of the week.

Engineering experts have said that while the tower remains stable, and it is safe for people to live, work and study nearby, its condition will worsen over time and there is no realistic prospect of bringing it back into use.

The latest advice issued to the government in September was that the building, or the part of it that was significantly damaged, should be taken down.

Meanwhile, another campaign group, Grenfell United, claimed Ms Rayner had not given a reason behind her decision during the meeting and refused to say how many of the victims’ families and survivors had been consulted.

In a statement, it said: “But judging from the room alone – the vast majority of whom were bereaved – no one supported her decision. But she claims her decision is based on our views.

“Ignoring the voices of bereaved on the future of our loved ones’ gravesite is disgraceful and unforgivable.”

Grenfell Next of Kin expressed a different opinion, suggesting the decision by Ms Rayner “must have been difficult” and adding that “all the previous Secretaries of State [for Housing, Communities and Local Government] avoided making a decision despite the harm it did to us and the community.”

Local Labour MP Joe Powell also defended Ms Rayner posting on X that following “intensive engagement with our community… the decision to start planning for the Tower to come down has not been taken lightly”.

What is left of the tower has stood in place since the tragedy, with a covering on the building featuring a large green heart accompanied by the words “forever in our hearts”.

Views have varied on what should happen to the site.

Some of the bereaved and survivors feel the tower should remain in place until there are criminal prosecutions over the failings which led to the disaster.

The final report of the Grenfell Tower Inquiry, published in September, concluded the fire was the result of “decades of failure” by government and the construction industry to act on the dangers of flammable materials on high-rise buildings.

The west London tower block was covered in combustible products because of the “systematic dishonesty” of firms who made and sold the cladding and insulation, inquiry chairman Sir Martin Moore-Bick said.

He said the “simple truth” is that all the deaths were avoidable and that those who lived in the tower were “badly failed” by authorities “in most cases through incompetence but, in some cases, through dishonesty and greed”.

However, the Metropolitan Police said last year that decisions on criminal charges for the Grenfell Tower blaze are not expected until the end of 2026.

It would mean a near 10-year wait for justice if anyone is ultimately charged – a period of time described by families as “unbearable”.

The disaster was Britain’s deadliest residential fire since the Second World War and began a national reckoning over the safety and conditions of social housing and tower blocks.

Separately, the Grenfell Tower Memorial Commission has been consulting on plans for a permanent memorial in the area of the tower.

A shortlist of five potential design teams was announced last month, with a winner expected to be selected this summer to enable a planning application to be submitted in late 2026.

A government spokesperson said: “The priority for the deputy prime minister is to meet with and write to the bereaved, survivors and the immediate community to let them know her decision on the future of the Grenfell Tower.

“This is a deeply personal matter for all those affected, and the deputy prime minister is committed to keeping their voice at the heart of this.”

Politics

Conservatives pledge to tighten immigration rules in Reform fightback

Published

1 hour ago

February 6, 2025

admin

Conservatives pledge to tighten immigration rules in Reform fight back

The Conservative Party is pledging to tighten immigration rules after Reform topped a landmark poll for the first time earlier this week.

In her first major policy announcement as Tory Party leader, Kemi Badenoch is pledging to double the amount of time an immigrant needs to have been in the UK before claiming indefinite leave to remain from five to 10 years.

In order to claim indefinite leave to remain after 10 years, the individual must also meet new, tightened conditions.

These include not having claimed benefits or used social housing during the entire qualification period, not having a criminal record and being able to demonstrate that their household would be a “net contributor”.

Ms Badenoch accused Labour of being “not serious about tackling immigration” and said there needs to be a “new approach”.

“Our country is not a dormitory, it’s our home,” she said.

“The right to citizenship and permanent residency should only go to those who have demonstrated a real commitment to the UK. That’s why we should double the length of time before people can qualify for indefinite leave to remain from five to 10 years.

“The Conservative Party is under new leadership. We’re going to tell the hard truths about immigration.

“The pace of immigration has been too quick and the numbers coming too high for meaningful integration. We need to slow down the track for citizenship. A UK passport should be a privilege not an automatic right.

“Far from reducing the number of people coming into Britain, the Labour government are presiding over an incoming disaster.

“The Border Security Bill will actually make it easier for illegal immigrants to stay in the UK, let alone legal migrants. No one can trust Labour on immigration.”

The announcement comes just days after Reform topped a Sky News/YouGov poll for the first time as the party continues to shake up British politics.

The poll, taken on 2 February and 3 February, showed Nigel Farage’s party has edged in front on 25%, with Labour pushed into second on 24% and the Tories on 21%.

It also put the Lib Dems on 14% and Greens on 9%.

All the polling moves that push Reform UK to the top for the first time this week are within the margin of error and the overall picture remains unchanged – with Britain in a new period of three party politics in the polls.

According to the poll, one in five Tory voters at the last election would now vote for Reform.

The Sky News/YouGov poll also found Kemi Badenoch has slipped behind Nigel Farage when voters are asked whether they have a favourable or unfavourable opinion of the leaders.

Last month, Badenoch had a net favourability rating of -25, but that has now dropped to -29 this month.

This puts her below Farage, who had a net favourability rating of -32 last month, which has now risen to -27 this month.

Labour’s border security minister Dame Angela Eagle said: “While [the Conservatives] scramble around for relevance, this Labour government is getting on with clearing up the mess they left behind – raising deportations, returns and removals to the highest rate in six years, increasing the number of illegal working raids and cutting the costs of the asylum system.”