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ApoA-1 Milano 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]
Discovery
Discovered by accident, the mutation was found to be present in about 3.5% of the population of Limone sul Garda, a small village in northern Italy. It has been traced to a mutation in a single man who had lived in the village in the 1700s and passed it on to his offspring.[2]
It is characterized by the replacement of a single amino acid at R173C.[3]
Use as treatment
Due to its enormous apparent efficacy, some have speculated that development of synthetic apoA-1 Milano may be a key factor in eradicating coronary heart disease.
Proof of efficacy in both animals and humans was performed by the Esperion company, a high tech venture capital start-up, which spent many millions of dollars over several years culminating in a single human trial which showed impressively rapid efficacy by IVUS of coronary arteries, but managed to produce only enough of the apoA-1 protein over several years of effort to partially treat 30 out of the 45 people in the randomized trial, once weekly for a total of 5 weeks. The trial results were published in JAMA and multiple references are available on the net: the Apo A-1 Milano trial.
From a business standpoint, producing an expensive protein which has to be administered IV to be effective and has to be given repeatedly and indefinitely is not a good business model. However, it did provide some proof of concept and the impetus to develop a mass market HDL improving product.
Given the ground breaking work and promising future product concepts Esperion was working on, Pfizer purchased and internalized the Esperion company shortly before the Apo A-1 Milano trial was published in hopes of developing a more effective treatments than their current product Lipitor.
No drugs are currently commercially available based on apoA-1 Milano. Rights to apoA-1 Milano were acquired in 2003 by Pfizer. Clinically known as ETC-216, Pfizer has not moved trials forward, probably because the protein is complex and very expensive to produce and must be administered intravenously, thus limiting its application as compared to oral medications [4].
References
- ^ 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" (PDF). J. Clin. Invest. 66 (5): 892–900. doi:10.1172/JCI109956. PMID 7430351, http://www.jci.org/articles/view/109956/pdf. Full text at PMC: 371523
- ^ 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. PMID 3936350. Full text at PMC: 1684746
- ^ Weisgraber KH, Rall SC, Bersot TP, Mahley RW, Franceschini G, Sirtori CR (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. PMID 6401735, http://www.jbc.org/cgi/reprint/258/4/2508.
- ^ Sue Hughes, ERASE: New HDL Mimetic Shows Promise, Heartwire
External links
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