Primarily, two types of chemistries have been used to modify the antisense oligonucleotide and increase its stability and/or uptake by cells: 2′-O-methylated oligonucleotides, usually coupled to a cholesterol group9 and, more recently, oligonucleotides containing locked

nucleic acid (LNA) residues (Fig. 1). A LNA antisense oligonucleotide binding to the 5′ part of miR-122 (SPC3649; Santaris Pharma, Hoersholm, Denmark) has been shown to be efficient via mouse models in confirming that blocking miR-122 results in a decrease in cellular targets involved in cholesterol biogenesis.10 Next, the inhibition of miR-122 and its effect on cholesterol levels was confirmed in nonhuman primates.11 The stage was set for testing the Selleck GS1101 real effect of blocking miR-122 on HCV infection in a primate model. Following up on these investigations, miRNA-122 has now been shown to be a target for antiviral intervention. In a report CHIR-99021 clinical trial this month in Science, Robert Lanford and colleagues showed that the inhibition of miR-122 in chimpanzees leads

to long-lasting suppression of HCV viremia (Fig. 1).12 Using high and low doses of the SPC3649 oligonucleotide, they demonstrated that treatment of chronically HCV-infected animals with the LNA oligonucleotide results in a marked and sustained decrease of HCV RNA in both serum and liver. The sequestration of miR-122 by the LNA oligonucleotide was confirmed, as well as the strong reduction of free miR-122 levels for the high-dose animals. No rebound in viremia was observed during the treatment, and no adaptive mutations were found in the miR-122–binding sites. The analysis of the liver transcriptome revealed a marked down-regulation of IFN-regulated genes, which confirmed that the endogenous IFN pathway in the liver was Rebamipide normalized after inhibition of HCV RNA. Finally, as expected, the antagonism of miR-122 resulted in a strong decrease in serum cholesterol (Fig. 1). Besides that effect, no measurable toxic effect in the liver could be attributed to SPC3649. What are the clinical implications of this landmark study? The results of Lanford et al. clearly show that antagonism of miR-122 by the LNA oligonucleotide

SPC3649 leads to marked suppression of viremia in chronically HCV-infected chimpanzees and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound suggests that targeting miRNA-122 by antagonists holds promise as a novel antiviral therapy. A potential advantage compared to therapeutic strategies that target viral factors may be the high barrier to resistance, as demonstrated by the lack of rebound in viremia during the treatment and the lack of adaptive mutations in the two miR-122 seed sites of the HCV 5′ noncoding region. Furthermore, conservation of both miR-122 seed sites in all HCV genotypes and subtypes suggests that such therapy will most likely be genotype-independent.