ApoA-1 Milano 5209859 214602994 2008-05-24T10:17:37Z 58.96.40.42 '''ApoA-1 Milano''' is a naturally occurring [[genetic mutation|mutated]] variant of the [[apolipoprotein A1]] protein found in human [[high density lipoprotein|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.<ref name="pmid7430351">{{cite journal |author=Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW |title=A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family |journal=J. Clin. Invest. |volume=66 |issue=5 |pages=892-900 |year=1980 |pmid=7430351 |doi=10.1172/JCI109956 |url=http://www.jci.org/articles/view/109956/pdf |format=PDF}} {{PMC|371523}}</ref> ==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.<ref name="pmid3936350">{{cite journal |author=Gualandri V, Franceschini G, Sirtori CR, ''et al'' |title=AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission |journal=Am. J. Hum. Genet. |volume=37 |issue=6 |pages=1083-97 |year=1985 |pmid=3936350}} {{PMC|1684746}}</ref> It is characterized by the replacement of a single [[amino acid]] at R173C.<ref name="pmid6401735">{{cite journal |author=Weisgraber KH, Rall SC, Bersot TP, Mahley RW, Franceschini G, Sirtori CR |title=Apolipoprotein A-IMilano. Detection of normal A-I in affected subjects and evidence for a cysteine for arginine substitution in the variant A-I |journal=J. Biol. Chem. |volume=258 |issue=4 |pages=2508-13 |year=1983 |pmid=6401735 |url=http://www.jbc.org/cgi/reprint/258/4/2508 |format=PDF}}</ref> ==Use as treatment== {{Unreferencedsection|date=April 2008}} 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]]. [[List of pharmaceutical compound number prefix|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 [[intravenous]]ly, thus limiting its application as compared to oral medications <ref>Sue Hughes, [http://www.medscape.com/viewarticle/554164 ERASE: New HDL Mimetic Shows Promise], Heartwire</ref>. ==References== <references/> ==External links== * [http://www.time.com/time/2004/cholesterol/drano.html Time.com: Drano for the Heart] * [http://www.usatoday.com/news/health/2006-01-08-heart-disease-cover_x.htm USATODAY.com: 'Next frontier' in heart disease: Undoing it] * [http://heartdisease.about.com/cs/coronarydisease/a/plaquebuster.htm About.com: Synthetic HDL shrinks coronary artery plaques] [[Category:Hypolipidemic agents]]