A strategy developed by Massachusetts General Hospital (MGH)-based investigators to increase levels of beneficial high-density lipoprotein (HDL) has been shown for the first time to be effective in non-human primates. The approach uses tiny antisense sequences to block the action of microRNAs that would otherwise inhibit a protein required for generation of HDL, the “good cholesterol” that helps remove harmful lipids from the body. The report appears in the November 20 Science Translational Medicine.
“We have found that targeting both members of the miR-33 microRNA family with a tiny, 8-nucleotide anti-microRNA can increase HDL levels by almost 40 percent,” says Anders Näär, PhD, of the MGH Center for Cancer Research, who led the study. “This sets the stage for new therapeutic strategies to treat cardiovascular disease in humans and provides a template for targeting other disease-associated microRNA families.”
Major regulators of gene expression, microRNAs are segments made up of 20- to 24-nucleotides that bind to complementary strands of messenger RNA, blocking their translation into proteins. A 2010 study led by Näär identified two related microRNAs – miR-33a and miR-33b – that inhibit a protein called ABCA1, which is essential for both the generation of HDL and for the transport of lipids to the liver. Treatment with miR-33-blocking antisense molecules was able to increase HDL levels in mice, but rodents have only one form of the microRNA. If the two versions of miR-33 carried by humans and other primates have redundant effects – that is if they both act to inhibit ABCA1 – blocking only a single version would be ineffective.
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