2'-O-Methoxyethyl/2'-Fluoro Modified Oligonucleotides Result in More Potent Inhibition of micro RNA-122 in Vivo: A Target implicatedin HCV Replication

Abstract

MicroRNAs are endogenous 20-24 nt small non-codingRNAs that have profound roles in multiple developmental and cellular processes. Dysregulation of microRNAs can lead to a host of pathologies suggesting that microRNAs could be important for therapeutic intervention in cancer, metabolic diseases, autoimmune disorders and viral diseases. Through recent studies,mir-122 has emerged as a potential target for metabolic diseases and HCY. Chemical modifications are essential to achieve clinically relevant potency and efficacy andtherapeutic index of anti-miRNA oligonucleotides. Wehave evaluated more than 65 chemically-modified ASOs for their ability to inhibit the activity of miR-122 inmice. Inhibition of miR-122 with ASOs resulted inincreased levels of miR-122 target gene mRNAs in theliver, as well as lowering of plasma cholesterol in a dose dependant manner. The current investigation led to the identification of a chimeric 2′Fluoro/2′-O-methoxyethyI(2'OME) modified motif with improved efficacy and 5-10 fold improvement in potency compared to LNA/DNAmodified and uniform 2′-MOE-PS compounds. Theseefforts have identified significantly improved anti-miR-122 ASOs for further evaluation as anti-HCV therapeutic agents.