MicroRNA Therapy Raises HDL Levels in Nonhuman-Primate Model

Blocking the activity of a specific microRNA (miRNA) in a nonhuman primate model increased the circulation of HDL (high-density lipoprotein) while lowering the levels of VLDL (very low-density lipoprotein) triglycerides, changes that reduce the risk of developing cardiovascular disease.

Recent studies in mice had shown that inhibiting the activity of the microRNA miR-33a was an effective strategy for raising plasma HDL levels. MiR-33a represses the genes responsible for encoding the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. However, extrapolation of these results to large mammals is difficult, since these animals have two forms of miR-33 (a and b), while mice have only the miR-33a form. Therefore, investigators at Wake Forest Baptist Medical Center (Winston-Salem, NC, USA) conducted a series of experiments to study the effect of blocking both miR-33a and miR-33b in an African green monkey model.

They reported in the October 19, 2011, online edition of the journal Nature that systemic delivery of an anti-miRNA oligonucleotide that targeted both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. MiR-33 antagonism in this nonhuman-primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation and reduced the expression of genes involved in fatty acid synthesis, resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides. The decrease in triglycerides was apparent after four weeks and reached a maximum reduction of 50%.

“The study was conducted because there is a very strong inverse correlation between the amount of HDL (good cholesterol) and heart disease," said contributing author Dr. Ryan Temel, assistant professor of pathology and lipid sciences at Wake Forest Baptist Medical Center. “The higher your level of HDL, the lower is your risk of developing cardiovascular disease. Currently, however, there are few therapies that significantly raise HDL.”

“Coronary artery disease is the number one killer of people in the United States,” said Dr. Temel. “It is 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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Wake Forest Baptist Medical Center