Could triglyceride metabolic pathway gene hold key to heart attack reduction? - Printable Version
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Could triglyceride metabolic pathway gene hold key to heart attack reduction? - mtwalsh01 - 06-23-2014
Could the Isis Pharmaceuticals trial drug ISIS-APOCIIIRx, which is currently in Phase 2 trials for the rare disease familial chylomicronemia syndrome (FCS), have wider implications for reduction of heart disease risk? The results of two new studies in the New England Journal of Medicine, from research groups in the USA and in Denmark, suggests that this may be the case.
ISIS-APOCIIIRx targets the APOC3 protein, a key mediator in triglyceride metabolism. Triglycerides are elevated to dangerously high levels in FCS. Until now, there has been controversy about whether triglycerides, which tend to be elevated in in people with heart attacks, were a causative agent or simply associated with other risk-associated factors. The doubt was increased when trials of drugs that caused a small reduction in triglycerides failed to have any effect on heart attack rates. However, the two recent studies appear to have ended the speculation as they point to a number of mutations in the APOC3-encoding gene which are associated with both an approximately 40% reduced level of triglycerides and a 40% reduction in heart attack risk. The results of the two independent studies were “eerily consistent”, according to the senior author on the American paper, Dr. Sekar Kathiresan of Massachusetts General Hospital and the Broad Institute.
A previous smaller study from the University of Maryland in 2008 on Amish people had shown that one in twenty Amish carried a mutation in APOC3 compared to one in 150 in the general American population and had substantially reduced triglyceride levels. The data, while interesting, were difficult to extrapolate to determine any impact on heart disease risk due to both the need to follow people over a substantial time period and also cultural reasons such as the tendency for Amis people to attend hospital less frequently than the general population, making cause of death more difficult generally to establish. The new studies were much larger, with the American study from researchers at the Broad Institute of Harvard and M.I.T mapping genes from 3734 Americans and the Danish study from researchers in Copenhagen University Hospital, using data from 75,725 people to investigate whether low triglyceride levels associated with reduced heart attack risk. In both studies APOC3 stood out as mutations in the gene encoding it was associated with both reduced triglycerides and reduced heart attack risk of between 36% to 40%.
The findings of these studies point the way to the development of new drugs for heart attack reduction for the first time essentially since the development of LDL-cholesterol targeting statins in the 1980s. This is where the Isis Pharmaceuticals ISIS-APOCIIIRx may come in. While the drug is currently in Phase 2 trials for FCS, and is targeted at APOC3, the company is keeping its options open regarding a wider indication in heart disease. However, the kind of huge, long-lasting study that would be needed would be beyond the scope of a small company like Isis and would require the resources of a larger company. Isis CEO Stanley Cooke said to Bloomberg"We're weighing how we want to take full advantage of this breakthrough, and as we do that we have to consider the potential broader development of the follow on product…We have a great deal of licensing interest for this drug." However, some industry analysts suggest that the potential of this drug and the underperformance of some other Isis products leaves them vulnerable to a hostile takeover. Whatever the outcome, t
he results of these important new studies raise hope of a new strategy to tackle the risk of heart disease.
The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease. N Engl J Med (18 June 2014), doi:10.1056/nejmoa1307095
Jørgensen, A. B., R. Frikke-Schmidt, B. G. Nordestgaard, and A. Tybjærg-Hansen. N Engl J Med (18 June 2014), doi:10.1056/nejmoa1308027
Kolata, G. In Single Gene, a Path to Fight Heart Attacks. New York Times (18 June 2014), available from http://www.nytimes.com/2014/06/19/health/scientists-identify-mutations-that-protect-against-heart-attacks.html?module=Search&mabReward=relbias%3Ar&assetType=nyt_now&_r=1