Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides

Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality in westernized countries, despite optimum medical therapy to lower LDL cholesterol. The pursuit of novel therapies to target this residual risk has focused on raising levels of HDL cholesterol in order to exploit its atheroprotective effects1. MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and are thus a new class of targets for therapeutic intervention2. MicroRNA-33a and b (miR-33a/b) are intronic microRNAs embedded in the sterol response element binding protein genes SREBF2 and SREBF13–5, respectively, that repress expression of the cholesterol transporter ABCA1, a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL3–5 and protecting from atherosclerosis6, however extrapolation of these findings to humans is complicated by the fact that mice lack miR-33b which is present only in the SREBF1 gene of higher mammals. Here we show in African green monkeys that systemic delivery of an anti-miR oligonucleotide that targets both miR-33a and miR-33b increases hepatic expression of ABCA1 and induces a sustained increase in plasma HDL over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in the oxidation of fatty acids (CROT, CPT1A, HADHB, PRKAA1) and reduced genes involved in fatty acid synthesis (SREBF1, FASN, ACLY, ACACA), resulting in a marked suppression of plasma VLDL triglyceride levels, a finding not previously observed in mice. These data establish, in a model highly relevant to humans, that pharmacological inhibition of miR-33a and b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglycerides for the treatment of dyslipidemias that increase cardiovascular disease risk.

Hepatic ABCA1 Expression Improves β-Cell Function and Glucose Tolerance

“…ABCA1 is considered an important target for the development of such HDL-increasing strategies. Increased ABCA1 concentrations due to treatment with liver X receptor agonists or microRNA-33 inhibitors have been shown to increase plasma HDL-cholesterol concentrations in mice and monkeys, and these interventions reduce atherosclerosis in hyperlipidemic mice (23)(24)(25). Our data suggest that such drugs may also be beneficial and improve b-cell function in diabetes.…”

“…HDL-increasing therapies for the treatment of patients with dyslipidemia are currently under development (23)(24)(25). ABCA1 is considered an important target for the development of such HDL-increasing strategies.…”

Identification of potential microRNA–target pairs associated with osteopetrosis by deep sequencing, iTRAQ proteomics and bioinformatics

“…The cultures were harvested and analyzed by western bolt or the Dual-Glo Luciferase Assay System (Promega) after 48 h, and the activity of Firefly luciferase was normalized to the activity of Renilla luciferase as a control miRNA-target pairs associated with osteopetrosis M Ou et al for transfection efficiency. 16 All of these experiments were repeated two to three times.…”

Strategies to deliver microRNAs as potential therapeutics in the treatment of cardiovascular pathology

“…At present, Miragen Therapeutics develops three (Rayner et al, 2011a(Rayner et al, , 2011b. Hopefully, clinical testing of chemically modified oligonucleotide inhibitors of atherogenic miRNAs is not far to start soon.…”