Progress in understanding the genetics of CAD lead to more therapeutic targets

Progress in understanding the genetics of CAD lead to more therapeutic targets -

progress in understanding the genetic disease of the coronary artery, or CAD, will revitalize the field and lead to more therapeutic targets for new drugs to fight against this common disease, suggests a genetics expert from medical Perelman school of the University of Pennsylvania in a perspective article in the new issue of science Translational Medicine .

Daniel J. Rader, MD, president of the Department of Genetics and associate director of the Translational Medicine Institute and Therapeutics, says the delay in search for new drugs for the heart could be jump-a started a hunt for wide angle for relevant variants in human genetics.

According to the American heart Association, the rate of heart disease death fell about 39 percent in the last 10 most recent years for which statistics are available. However, heart disease is the leading cause of death in the United States, killing nearly 380,000 people per year.

While progress has been made in reducing the risk of heart disease, with the highest intake of statins to reduce cholesterol levels of low density lipoprotein (LDL-C) in millions the burden of disease remains high. "Despite this unmet need clear, however, many biopharmaceutical companies have begun to retreat from efforts to discover and develop therapies for this common disease," wrote Rader, citing seven drugs that failed in Phase 3 clinical trials in the last three to five years.

the most important issue facing the development of new treatments for heart disease is trust before expensive human trials are underway as the target for a new drug has a high probability of success in disease reduction. Atherosclerotic animal models, however, has not proven to predict new therapies that are effective in humans. However, Rader said, drug targets based on human genetics can provide greater confidence that a therapy targeted to a particular channel will show a clinical benefit in reducing major cardiovascular events in people. As with the recent successes in the cancer immunotherapy, targeted personalized approach to developing new treatments has proved attractive to large pharmaceutical companies.

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Human genetic data strongly the concept that reducing LDL-C by any means associated with lower cardiovascular risk. This association is consistent with the LDL-C is a causal factor in the development of cardiovascular diseases. Indeed, the discovery that mutations in the PCSK9 gene reduce LDL-C and protect against CAD has launched a major effort to develop PCSK9 inhibitors, significantly reduced LDL-C and are in advanced clinical development.

Similar genetic data for triglycerides were published recently, which suggests that specific proteins regulating this chemical in the blood could be viable therapeutic targets. On the other hand, human genetic data provide little support to raise high-density lipoprotein (HDL-C), because the genetic variants associated with increased HDL-C are generally not associated with decreased cardiovascular risk.

Although circulating biomarkers such as LDL and triglycerides, commonly found in standard panels of blood lipids, are useful to guide drug development programs focused on the reduction of CAD, Rader argues that many genetically validated target for CAD will be no bypassing established biomarkers. "Some of the most interesting new target for atherosclerotic cardiovascular disease is likely to come from genetic studies of common and rare variants, comparing people with early disease with those who are free of the disease," says Rader.

He cites studies common variants associated with CAD who gave almost 50 discrete genetic loci of the entire genome that are statistically significantly associated with CAD. Less than a third are associated with these traditional risk factors such as levels LDL-C or blood pressure, leaving over 30 loci not associated with traditional measurable risk factors.

Rader cites a study in the Lancet in 2011, in collaboration with Penn colleague Muredach P. Reilly, MBBCh , MSCE, associate Professor of medicine and pharmacology, who has identified a new locus, ADAMTS7, a gene already implicated in arthritis, which has been associated with risk of developing CAD.

ADAMTS7 is a metalloproteinase, an enzyme expressed in blood vessels. Rader suggests that if we could show that genetically reduced activity of ADAMTS7 protects against CAD, it would provide convincing support for the concept of pharmacological inhibition of this enzyme, "Situations of this kind, in which the loss-of variants of function gene are associated with protection from CAD are particularly compelling because they suggest that pharmacological inhibition of these proteins could be expected to reduce the risk. "

The wealth of new genetic discoveries in recent years, combined with those more likely to come, provided new targets and potential has attracted the attention of the biopharmaceutical industry, says Rader. Indeed the partnership drugs Accelerate, a partnership between the national Institutes of health and 10 biopharmaceutical companies (Rader co-led the working group for type 2 diabetes), was recently formed to take advantage of human genetics to discover and validate new therapeutic targets.