Oct. 31, 2011 A new therapy being studied in non-human primates by researchers at Wake Forest Baptist Medical Center and colleagues is demonstrating promise as a potential tool for combating cardiovascular disease by increasing good cholesterol and lowering triglycerides in the blood.
Supported by the National Institutes of Health and the Canadian Institutes of Health Research, the preclinical findings appear in this week's issue of the journal Nature.
"The study was conducted because there is a very strong inverse correlation between the amount of HDL (good cholesterol) and heart disease," said co-principal investigator Ryan Temel, Ph.D., an assistant professor of pathology and lipid sciences at Wake Forest Baptist. "The higher your level of HDL, the lower your risk of developing cardiovascular disease. Currently, however, there are few therapies that significantly raise HDL."
While there are several effective therapies available on the market for lowering LDL, or bad cholesterol, modern medicine has yet to find a good way to raise HDL, Temel said. "Even if you take a statin or some other therapy to lower your LDL, the risk of having coronary heart disease is still around 50 percent. There's clearly a lot of room left for improvement."
Temel and colleagues from NYU Langone Medical Center and Regulus Therapeutics Inc., a biopharmaceutical company, are studying a new drug that targets microRNA-33 (miR-33). MiR-33 is a small RNA molecule that reduces HDL and increases triglyceride production. In previous studies in mice, the drug has been effective in promoting atherosclerotic plaque regression and increasing HDL.
For the current study, researchers tested the drug, anti-miR-33, in non-human primates and found that it increased HDL cholesterol and lowered triglycerides. Non-human primates were selected this time because rodents only express one form of miR-33 -- miR-33a -- while humans and non-human primates have two types of miR-33 -- miR-33a and miR-33b.
In the study, use of the drug resulted in a maximum HDL cholesterol increase of 50 percent after eight weeks that was sustained throughout the remainder of the 12-week study. Anti-miR-33a/b treatment in the non-human primate model also increased the expression of miR-33 target genes involved in fatty acid breakdown resulting in suppressed triglyceride levels, a finding not previously observed in mice. The decrease in triglycerides was apparent after four weeks and reached a maximum reduction of 50 percent.
This pre-clinical study was the first to demonstrate that inhibiting miR-33a/b has a significant and sustained effect on both circulating HDL and plasma triglyceride levels, Temel said.
These findings indicate that miR-33a and miR-33b are key regulators of cholesterol and fatty acid metabolism, Temel added, and that an anti-miR-33 approach could directly impact atherosclerosis, as well as address important cardiovascular risk factors such low HDL and high triglycerides.
The researchers will next evaluate whether the drug has the ability to stimulate cholesterol movement out of the arteries, where it has accumulated and formed atherosclerotic lesions.
"Coronary artery disease is the number one killer of people in the United States," Temel said. "It's a very big problem. The ideal therapy would not only reduce cholesterol accumulation in the arteries by lowering bad cholesterol but also increase the removal of existing cholesterol in the arteries by elevating good cholesterol. The combination of a statin and anti-miR-33 could potentially be this therapy. While there is still a lot of work that needs to be done with this drug before it can ever be used in humans, anti-miR-33 is showing strong potential as a new therapy for reducing coronary heart disease risk."
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- Katey J. Rayner, Christine C. Esau, Farah N. Hussain, Allison L. McDaniel, Stephanie M. Marshall, Janine M. van Gils, Tathagat D. Ray, Frederick J. Sheedy, Leigh Goedeke, Xueqing Liu, Oleg G. Khatsenko, Vivek Kaimal, Cynthia J. Lees, Carlos Fernandez-Hernando, Edward A. Fisher, Ryan E. Temel, Kathryn J. Moore. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature, 2011; 478 (7369): 404 DOI: 10.1038/nature10486
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