Abstract IA20: Targeting of microRNAs for therapeutics

Abstract

Abstract microRNAs act as important post-transcriptional regulators of gene expression by mediating mRNA degradation and translational repression. Moreover, there is ample evidence that perturbations in the levels of individual or entire families of miRNAs are strongly associated with the pathogenesis of a wide range of human diseases. Besides cancer, miRNAs have also been implicated in viral infections, cardiovascular and muscle diseases and CNS disorders. Thus, disease-associated miRNAs represent a potential new class of targets for oligonucleotide-based therapeutics, which may yield patient benefits unobtainable by other therapeutic approaches. LNA is a bicyclic high-affinity RNA analogue, in which the ribose ring is locked in an RNA-like, N-type (C3′-endo) conformation by the introduction of a 2′-O,4′-C methylene bridge. Transfection of LNA-modified antimiR oligonucleotides into cells results in potent and specific inhibition of miRNA function with concomitant derepression of direct target mRNAs. In addition, systemically delivered, unconjugated LNA-antimiRs with a phosphorothioate backbone show high metabolic stability and uptake in many tissues in mice, coinciding with long-term miRNA silencing in vivo. These findings support the utility of LNA-modified antimiR oligonucleotides in the development of therapeutic strategies aimed at pharmacological inhibition of disease-associated miRNAs. We will describe recent progress in targeting of disease-implicated miRNAs for therapeutics using LNA-antimiRs and present an update on the clinical development of antimiR-122 for treatment of hepatitis C virus infection. Citation Format: Sakari Kauppinen. Targeting of microRNAs for therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA20.