Discovering the first microRNA-targeted drug

Abstract

MicroRNAs (miRNAs) are important post-transcriptional regulators of nearly every biological process in the cell and play key roles in the pathogenesis of human disease. As a result, there are many drug discovery programs that focus on developing miRNA-based therapeutics. The most advanced of these programs targets the liver-expressed miRNA-122 using the locked nucleic acid (LNA)-modified antisense oligonucleotide miravirsen. Here, we describe the discovery of miravirsen, which is currently in phase 2 clinical trials for treatment of hepatitis C virus (HCV) infection.

Figure 1.

Key findings in miRNA research and the discovery of the first miRNA-targeted drug, miravirsen. The timeline indicates the key events from the discovery of the first microRNA, lin-4, in C. elegans to clinical testing of miravirsen in HCV-infected patients.

Figure 2.

A model for interaction of miR-122 with the 5′ UTR of the HCV RNA and miravirsen’s mechanism of action. (A) The liver-expressed miR-122 is an important host factor for HCV and interacts with the 5′ untranslated region (UTR) of the virus genome by binding to two miR-122 seed sites in association with Ago2. By forming an oligomeric miR-122-HCV complex, miR-122 protects the 5′ UTR from nucleolytic degradation, thereby promoting viral RNA stability and propagation (Jopling et al., 2005; Machlin et al., 2011; Shimakami et al., 2012). (B) Miravirsen is a high-affinity 15-mer LNA-modified antimiR oligonucleotide (red uppercase, LNA modifications; lowercase, DNA) that acts by sequestering mature miR-122, leading to inhibition of miR-122 function and thereby suppression of HCV.