ApoA-1 Milano

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Apolipoprotein A-1 Milano (also ETC-216, now MDCO-216) is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA1 Milano was first identified by Dr. Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels. [1]

Contents

Discovery

The ApoA-1 Milano mutation was found by University of Milan researchers after their 1974 investigation of a low HDL / high triglyceride phenotype exhibited by Valerio Dagnoli of Limone sul Garda, a small village in northern Italy. [2] : 163  Limone had only 1,000 inhabitants at the time and when blood tests were run on the entire population of the village, the mutation was found to be present in about 3.5% of the local population. [2] : 163  The mutation was traced to one man, Giovanni Pomarelli, [3] who was born in the village in 1780 and passed it on to his offspring. [4] [2] : 163  [5] It is characterised by the replacement of arginine by cysteine at position 173 (197 for UniProt). [6] The mutation is known in single nucleotide polymorphism (SNP) nomenclature as rs28931573. [7]

In the 1990s, researchers at the Cedars-Sinai Medical Center showed that injection of a synthetic version of the mutant ApoA-1 into rabbits and mice could reverse vascular plaque buildup. [2] : 164 

Efficacy in Apo A-I/Apo E null mice

Apo A-I Milano has been shown to reduce atherosclerosis in animal models and in a small phase 2 human trial. Recombinant adeno-associated virus 8 (AAV8) mediated Apo A-I Milano gene therapy in combination with low-cholesterol diet induces rapid and significant regression of atherosclerosis in mice. [8] [9]

Efficacy in humans

The first examination of using the mutant ApoA-1 in humans was conducted through a three way collaboration between the University of Milan and the companies Pharmacia and Upjohn in 1996, focusing on treatment of atherosclerosis. [2] : 164 

The ApoA-1 Milano Trial, published in JAMA in 2003, [10] was the first published placebo controlled, 2 dose level, trial in humans. This was a secondary prevention trial in that those included were individuals who presented to a participating hospital with unstable angina and agreed to consent to a rigorous trial, well beyond usual clinical practice testing and treatment, testing whether this HDL protein variant, which was so effective in animals, would also work in humans. This trial was initiated by Steven Nissen of the Cleveland Clinic after prompting by Roger Newton of Esperion to examine the effects of the mutant protein using intravascular ultrasound imaging. [2] : 164  Esperion provided the protein, code named ETC-216, for the duration of the trial. [10] : 2293 

Use as treatment

Due to its potential efficacy, it was speculated that development of synthetic ApoA-1 Milano might be a key factor in eradicating coronary heart disease. [11]

Esperion Therapeutics, a high tech venture capital start-up, demonstrated efficacy in both animals and humans, spending many millions of dollars over several years to conduct a single human trial which showed impressive and rapid efficacy by IVUS of coronary arteries. However, over the course of the project they produced only enough ApoA-1 Milano to partially treat thirty out of the forty-five people in the randomized trial, giving them one weekly dose each for five weeks. The results of the trial were published in JAMA (November 5, 2003). [10]

Hoping to develop a more effective treatment than their current product Lipitor, Pfizer purchased and internalized Esperion shortly before JAMA published the results of the Apo A-1 Milano trial.[ citation needed ]

Currently, no drugs based on ApoA-1 Milano are commercially available. Rights to ApoA-1 Milano were acquired in 2003 by Pfizer. Clinically known as ETC-216, Pfizer did not move trials forward, probably because the complex protein is very expensive to produce and must be administered intravenously, limiting its application compared to oral medications. [12] [13]

Subsequent Development

Pfizer, after the CETP agent torcetrapib failed in a large human safety trial, decided to exit the cardiovascular market in 2008, though they continue to market Lipitor aggressively.

Esperion, divested by Pfizer in 2008, [14] is back in business and continue to work on HDL mimetic therapies. [15] The company established an agreement with TransGenRx as a protein source. [16]

Calgary-based SemBioSys Genetics Inc. was a biotechnology company that was using Safflower to develop commercial quantities of ApoA-1 Milano.[ citation needed ] On October 11, 2011, SemBioSys Genetics signed a multi-product commercialization and platform collaboration agreement with Tasly Pharmaceuticals of Tianjin (China). In May 2012, SemBioSys terminated its operations and announced that Tasly had terminated their agreement. [17]

On 22 December 2009 The Medicines Company announced it had entered into an exclusive worldwide licensing agreement with Pfizer Inc. for ApoA-I Milano which it then renamed MDCO-216. [18] [19]

On the 12th of July 2010 The Medicines Company signed a pharmaceutical development and manufacturing contract with OctoPlus (Netherlands-based drug delivery and drug development company) to perform process development and clinical manufacturing of MDCO-216. [20] After a trial study failed to produce significant enough results compared to other drugs being tested, in 2016 The Medicines Company discontinued development of MDCO-216. [21]

Cardigant Medical is a Los Angeles-based biotech company that worked to commercialize ApoA-1 Milano to treat various vascular diseases. As of 2021, no new trials or commercialisation have been reported, and the web domain of the company website (http://www.cardigant.com Archived 2019-06-20 at the Wayback Machine ) has expired.

Related Research Articles

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

<span class="mw-page-title-main">Chylomicron</span> One of the five major groups of lipoprotein

Chylomicrons, also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%). They transport dietary lipids from the intestines to other locations in the body. ULDLs are one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. A protein specific to chylomicrons is ApoB48.

<span class="mw-page-title-main">Apolipoprotein</span> Proteins that bind lipids to transport them in body fluids

Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.

Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.

<span class="mw-page-title-main">Torcetrapib</span> Chemical compound

Torcetrapib was a drug being developed to treat hypercholesterolemia and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mortality in the treatment group receiving a combination of atorvastatin (Lipitor) and torcetrapib.

<span class="mw-page-title-main">Cholesteryl ester transfer protein</span> Mammalian protein found in Homo sapiens

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.

The lipid hypothesis is a medical theory postulating a link between blood cholesterol levels and the occurrence of cardiovascular disease. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease". It states, more concisely, that "decreasing blood cholesterol [...] significantly reduces coronary heart disease".

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

<span class="mw-page-title-main">Lipoprotein(a)</span>

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.

<span class="mw-page-title-main">Apolipoprotein AI</span>

Apolipoprotein AI(ApoA-I) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.

<span class="mw-page-title-main">Apolipoprotein C-III</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.

Endothelial lipase (LIPG) is a form of lipase secreted by vascular endothelial cells in tissues with high metabolic rates and vascularization, such as the liver, lung, kidney, and thyroid gland. The LIPG enzyme is a vital component to many biological processes. These processes include lipoprotein metabolism, cytokine expression, and lipid composition in cells. Unlike the lipases that hydrolyze Triglycerides, endothelial lipase primarily hydrolyzes phospholipids. Due to the hydrolysis specificity, endothelial lipase contributes to multiple vital systems within the body. On the contrary to the beneficial roles that LIPG plays within the body, endothelial lipase is thought to play a potential role in cancer and inflammation. Knowledge obtained in vitro and in vivo suggest the relations to these conditions, but human interaction knowledge lacks due to the recent discovery of endothelial lipase. Endothelial lipase was first characterized in 1999. The two independent research groups which are notable for this discovery cloned the endothelial lipase gene and identified the novel lipase secreted from endothelial cells. The anti-Atherosclerosis opportunity through alleviating plaque blockage and prospective ability to raise High-density lipoprotein (HDL) have gained endothelial lipase recognition.

<span class="mw-page-title-main">ABCA1</span> Mammalian protein found in Homo sapiens

ATP-binding cassette transporter ABCA1, also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.

<span class="mw-page-title-main">APOA5</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Familial dysbetalipoproteinemia</span> Medical condition

Familial dysbetalipoproteinemia or type III hyperlipoproteinemia is a condition characterized by increased total cholesterol and triglyceride levels, and decreased HDL levels.

Steven E. Nissen is an American cardiologist, researcher and patient advocate. He was chairman of cardiovascular medicine at the Cleveland Clinic, in Cleveland, Ohio.

<span class="mw-page-title-main">Apabetalone</span> Chemical compound

Apabetalone is an orally available small molecule created by Resverlogix Corp. that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD). In the phase II clinical trial ASSURE in patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels, apabetalone showed no greater increase in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels or incremental regression of atherosclerosis than administration of placebo, while causing a statistically significant greater incidence of elevated liver enzymes. However, pooled analysis of the effect of apabetalone in three phase II clinical trials ASSERT, ASSURE, and SUSTAIN demonstrated increases in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreases in the incidence of major adverse cardiac events (MACE). Reduction of MACE was more profound in patients with diabetes mellitus. In a short-term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone. An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015. The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.

References

  1. ↑ Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW (1980). "A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family". J. Clin. Invest. 66 (5): 892–900. doi:10.1172/JCI109956. PMC   371523 . PMID   7430351.
  2. 1 2 3 4 5 6 Li, Jie Jack (2009). Triumph of the Heart: The Story of Statins. Oxford University Press. ISBN   9780195323573.
  3. ↑ Maugh II, Thomas H. (November 5, 2003). "Drug for Heart Disease Called Breakthrough". Los Angeles Times .
  4. ↑ "Italian Gene Holds Hope for Unclogging Arteries". Los Angeles Times . October 17, 1994.
  5. ↑ Gualandri V, Franceschini G, Sirtori CR, et al. (1985). "AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission". Am. J. Hum. Genet. 37 (6): 1083–97. PMC   1684746 . PMID   3936350.
  6. ↑ Weisgraber KH, Rall SC, Bersot TP, Mahley RW, Franceschini G, Sirtori CR (25 February 1983). "Apolipoprotein A-IMilano. Detection of normal A-I in affected subjects and evidence for a cysteine for arginine substitution in the variant A-I" (PDF). J. Biol. Chem. 258 (4): 2508–13. doi: 10.1016/S0021-9258(18)32955-7 . PMID   6401735.
  7. ↑ "rs28931573 RefSNP Report". dbSNP - NCBI.
  8. ↑ Wang L., Tian F., Arias A., Yang M., Sharifi B. G., Shah P. K. (2015). "Comparative Effects of Diet-Induced Lipid Lowering Versus Lipid Lowering Along With Apo AI Milano Gene Therapy on Regression of Atherosclerosis". Journal of Cardiovascular Pharmacology and Therapeutics. 21 (3): 320–328. doi:10.1177/1074248415610216. PMID   26499098. S2CID   4138666.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Wang L, Tian F, Arias A, Yang M, Sharifi BG, Shah PK (2016). "Comparative Effects of Diet-Induced Lipid Lowering Versus Lipid Lowering Along With Apo A-I Milano Gene Therapy on Regression of Atherosclerosis". J Cardiovasc Pharmacol Ther. 21 (3): 320–328. doi:10.1177/1074248415610216. PMID   26499098. S2CID   4138666.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. 1 2 3 Nissen, Steven E.; Tsunoda, Taro; et al. (November 5, 2003). "Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes". JAMA . 290 (17): 2292–300. doi: 10.1001/jama.290.17.2292 . PMID   14600188. Open Access logo PLoS transparent.svg
  11. ↑ "What's the Deal With the New Plaque Dissolver?".
  12. ↑ ERASE: New HDL Mimetic Shows Promise, S Hughes, 2007, Heartwire
  13. ↑ http://www.drugdevelopment-technology.com/projects/etc/ ETC-216 - Phospholipid Therapy for Coronary Heart Disease (CHD) Patients
  14. ↑ url=http://www.ace-event.org/RNewtonAcePresentation.pdf%5B%5D
  15. ↑ "Esperion Product Candidates". Archived from the original on 2009-08-17.
  16. ↑ "TransGenRx Protein Therapeutics Technology to Support Research Related to Protein-Based HDL Therapies at Esperion". Archived from the original on 2012-02-13.
  17. ↑ "SemBioSys Announces First Quarter Results and Provides Update on Activities". 15 May 2012.
  18. ↑ "The Medicines Company | Development Pipeline | MDCO216". Archived from the original on 2010-08-08. Retrieved 2010-08-24.
  19. ↑ "The Medicines Company Acquires ApoA-I Milano From Pfizer". 22 December 2009.[ permanent dead link ]
  20. ↑ "The Medicines Company signs agreement with OctoPlus for MDCO-216 | TradingMarkets.com". www.tradingmarkets.com. Archived from the original on 14 October 2010. Retrieved 13 January 2022.
  21. ↑ "The Medicines Company Discontinues Development of MDCO-216, its Investigational Cholesterol Efflux Promoter | The Medicines Company". www.themedicinescompany.com. Archived from the original on 2017-10-09. Retrieved 2018-06-05.
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