MicroRNAs (miRs) are 21-23 nucleotide endogenously expressed RNAs. One of these, miR-122, is highly and specifically expressed in adult liver. A recent report by Jopling et al (Science 309, 1577-1581, 2005) demonstrates a role for miR-122 in replication of hepatitis C virus (HCV) RNA in human cells. Two other reports (Krutzfeldt et al, Nature 438, 685-689, 2005; Esau et al, Cell Metab, 3, 87-89, 2006) demonstrated inhibition of miR-122 in mouse liver using chemically modified antisense oligonucleotides (ASOs). In this application we propose to prepare and test chemically modified ASOs for inhibition of miR-122 in mouse hepatocytes, mouse liver and in a cellular assay for HCV replication. The ultimate goal of this research is development of an anti-miR-122 ASO therapeutic for treatment of HCV. Hepatitis C virus (HCV) infection can progress to significant liver disease; current treatments are often ineffective. We propose to identify a novel therapeutic to treat HCV in humans. A novel therapeutic offers the potential of reducing the severe and growing public health burden of HCV. MicroRNA biology is in its infancy and therapeutic applications for modulators of miRs are likely to be identified in the future. Because we are targeting a microRNA, we will also gain insight into the biological roles of microRNA and into methods for inhibition of miR activity. A long term benefit of this research will be application of what is learned in this study to development of anti-miR therapeutics for other indications. [unreadable] [unreadable] [unreadable]