Apolipoprotein A-1 Milano (also ETC-216, now MDCO-216) is a naturally occurring
mutated
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
variant of the
apolipoprotein A1
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.
Structure
''APOA1'' is located on chromosome 11, with its specific loc ...
protein found in human
HDL, the
lipoprotein
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, su ...
particle that carries
cholesterol from tissues to the liver and is associated with protection against
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
. ApoA1 Milano was first identified by Dr. Cesare Sirtori in
Milan
Milan ( , , Lombard: ; it, Milano ) is a city in northern Italy, capital of Lombardy, and the second-most populous city proper in Italy after Rome. The city proper has a population of about 1.4 million, while its metropolitan city has ...
, who also demonstrated that its presence significantly reduced
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
, even though it caused a reduction in HDL levels and an increase in
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
levels.
Discovery
The ApoA-1 Milano mutation was found by
University of Milan
The University of Milan ( it, Università degli Studi di Milano; la, Universitas Studiorum Mediolanensis), known colloquially as UniMi or Statale, is a public research university in Milan, Italy. It is one of the largest universities in Europe ...
researchers after their 1974 investigation of a low
HDL / high
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
phenotype exhibited by Valerio Dagnoli of
Limone sul Garda
Limone sul Garda ( Gardesano: ) is a town and ''comune'' in the province of Brescia, in Lombardy (northern Italy), at the western bank of Lake Garda.
History
Despite the presence of famous cultivations of lemons (the meaning of in Italian), the ...
, a small village in northern
Italy.
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.
[ The mutation was traced to one man, Giovanni Pomarelli, who was born in the village in 1780 and passed it on to his offspring.] It is characterised by the replacement of arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...
by cysteine at position 173 (197 for UniProt). The mutation is known in single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(SNP) nomenclature as rs28931573.
In the 1990s, researchers at the Cedars-Sinai Medical Center
Cedars-Sinai Medical Center is a nonprofit, tertiary, 886-bed teaching hospital and multi-specialty academic health science center located in Los Angeles, California. Part of the Cedars-Sinai Health System, the hospital employs a staff of over 2 ...
showed that injection of a synthetic version of the mutant ApoA-1 into rabbits and mice could reverse vascular plaque buildup.
Efficacy in Apo A-I/Apo E null mice
Apo A-I Milano has been shown to reduce atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no ...
in animal models and in a small phase 2 human trial. Recombinant adeno-associated virus
Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus '' Dependoparvovirus'', which in turn belongs to the family ''Parvoviridae''. They are small (approximately 26 nm in d ...
8 ( AAV8) mediated Apo A-I Milano gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
in combination with low- cholesterol diet
Diet may refer to:
Food
* Diet (nutrition), the sum of the food consumed by an organism or group
* Dieting, the deliberate selection of food to control body weight or nutrient intake
** Diet food, foods that aid in creating a diet for weight loss ...
induces rapid and significant regression of atherosclerosis in mice.
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
The University of Milan ( it, Università degli Studi di Milano; la, Universitas Studiorum Mediolanensis), known colloquially as UniMi or Statale, is a public research university in Milan, Italy. It is one of the largest universities in Europe ...
and the companies Pharmacia
Pharmacia was a pharmaceutical and biotechnological company in Sweden that merged with the American pharmaceutical company Upjohn in 1995.
History
Pharmacia company was founded in 1911 in Stockholm, Sweden by pharmacist Gustav Felix Grönfeldt ...
and Upjohn
The Upjohn Company was a pharmaceutical manufacturing firm founded in 1886 in Hastings, Michigan, by Dr. William E. Upjohn who was an 1875 graduate of the University of Michigan medical school. The company was originally formed to make ''friabl ...
in 1996, focusing on treatment of atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no ...
.
The ApoA-1 Milano Trial, published in JAMA in 2003, 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
Cleveland Clinic is a nonprofit American academic medical center based in Cleveland, Ohio. Owned and operated by the Cleveland Clinic Foundation, an Ohio nonprofit corporation established in 1921, it runs a 170-acre (69 ha) campus in Cleveland, ...
after prompting by Roger Newton of Esperion to examine the effects of the mutant protein using intravascular ultrasound imaging. Esperion provided the protein, code named ETC-216, for the duration of the trial.
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.
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
Intravascular ultrasound (IVUS) or intravascular echocardiography is a medical imaging methodology using a specially designed catheter with a miniaturized ultrasound probe attached to the distal end of the catheter. The proximal end of the cathe ...
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).
Hoping to develop a more effective treatment than their current product Lipitor
Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.
Common ...
, Pfizer purchased and internalized Esperion shortly before JAMA published the results of the Apo A-1 Milano trial.
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 intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
ly, limiting its application compared to oral medications.
Subsequent Development
Pfizer, after the CETP agent torcetrapib
Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause morta ...
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, is back in business and continue to work on HDL mimetic therapies. The company established an agreement with TransGenRx as a protein source.
Calgary-based SemBioSys Genetics Inc. was a biotechnology company that was using Safflower to develop commercial quantities of ApoA-1 Milano. 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.
On 22 December 2009 The Medicines Compan
announced it had entered into an exclusive worldwide licensing agreement with Pfizer Inc. for ApoA-I Milano which it then renamed MDCO-216.
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. 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.
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 ) has expired.
References
External links
Time.com: Drano for the Heart
{{DEFAULTSORT:Apoa-1 Milano
Hypolipidemic agents
Pfizer brands
1780 establishments in Italy
1974 in Italy
1974 in science
Mutated genes
Province of Brescia
Italian medical research
Health in Milan