Efficiency and Target Derepression of Anti-miR-92a: Results of a First in Human Study

Abstract

MicroRNA (miRNA) inhibition is a promising therapeutic strategy in several disease indications. MRG-110 is a locked nucleic acid-based antisense oligonucleotide that targets miR-92a-3p and experimentally was shown to have documented therapeutic effects on cardiovascular disease and wound healing. To gain first insights into the activity of anti-miR-92a in humans, we investigated miR-92a-3p expression in several blood compartments and assessed the effect of MRG-110 on target derepression. Healthy adults were randomly assigned (5:2) to receive a single intravenous dose of MRG-110 or placebo in one of seven sequential ascending intravenous dose cohorts ranging from 0.01 to 1.5 mg/kg body weight. MiR-92a-3p whole blood levels were time and dose dependently decreased with halfmaximal inhibition of 0.27 and 0.31 mg/kg at 24 and 72 h after dosing, respectively. In the high-dose groups, >95% inhibition was detected at 24-72 h postinfusion and significant inhibition was observed for 2 weeks. Similar inhibitory effects were detected in isolated CD31 + cells, and miR-92a-3p expression was also inhibited in extracellular vesicles in the high-dose group. Target derepression was measured in whole blood and showed that ITGA5 and CD93 were increased at a dose of 1.5 mg/kg. Single-cell RNA sequencing of peripheral blood cells revealed a cell typespecific derepression of miR-92a targets. Together this study demonstrates that systemic infusion of anti-miR-92a efficiently inhibits miR-92a in the peripheral blood compartment and derepresses miR-92a targets in humans.

The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling

“…However, recent progress in developing in vivo delivery systems for miRNAs brings this class of compounds back to the therapeutic forefront [41]. Administration of miRNAs or anti-miRNAs has been successfully tested in clinical phase I studies, specifically antimiR-92a in cardiovascular disease therapy and antimiR-132 in heart failure patients [41][42][43]. Successful inhibition of TLR4/NFκB signaling in fibroblast-like cells has been demonstrated in vitro by administration of miR-146, which also inhibits pro-fibrotic and inflammatory signaling pathways in renal fibrosis in vivo [44,45].…”

The promise of microRNA-based therapies in Alzheimer’s disease: challenges and perspectives

“…The miRNA-targeted pharmaceutical market is less advanced with numerous clinical trials currently underway (CDR132L, Cardior Pharmaceuticals GmbH; RG-012, Genzyme/Sanofi/Regulus Therapeutics; MRG-106, MRG-110, MRG-201, miRagen/Viridian Therapeutics; TargomiRs [172,[234][235][236]), yet none of them in AD. Miravirsen, an LNA-modified inhibitor of miR-122 with modified phosphorothioate backbone, to treat hepatitis C infection in the liver, was the first anti-miRNA drug to enter the clinic [225,228].…”

microRNAs as Novel Therapeutics in Cancer

“…MRG-201 (Remlarsen) by MiRagen Therapeutics (Boulder, CO, USA) is an LNA miR-29 mimic in phase 2 clinical trial (NCT03601052) that can limit the formation of fibrous scar tissue in the treatment of cutaneous fibrosis or idiopathic pulmonary fibrosis [123]. MRG-110 an LNA anti-miR-92-3p for the treatment of ischemic conditions is now in phase 1 (NCT03603431) [124]. Regulus Therapeutics Inc has already had two other products in clinical trials: (1) RG-012, an anti-miR-21 drug for the treatment of Alport syndrome that completed phase 1 (NCT03373786) in April 2019, and (2) RGLS4326 an anti-miR17 for autosomal dominant polycystic kidney disease (ADPKD) treatment that is currently on partial clinical hold by the U.S. Food and Drug Administration [125].…”