Публикации

Synthetic oligonucleotides: potential therapeutic applications and search of new targets in vitro and in vivo

Synthetic oligonucleotides attracted attention as the popular therapeutic agents for treatment human diseases. More than 15 drugs based on siRNAs and antisense oligonucleotides have already approved by US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [1].
Therapeutic nucleic acids are able to modulate gene expression with high efficacy, specificity and long-term duration of exposure. However, there are a number of problems associated with the oligonucleotides degradation by intracellular nucleases and the non-specificity of action, as well as the activation of immunity. New chemical modifications of oligonucleotides, methods of its targeted delivery and new targets for therapy are investigated to solve these issues [2]. In this work, we validated DDX3 RNA helicase as a target for therapy by siRNAs in hepatocytes, and also characterized a new potential biomarker - long non-coding RNA LL35 in vitro and in vivo. We demonstrated that the efficacy of RNAi-mediated DDX3 depletion in in vitro and in vivo affects the phenotype of hepatocytes, and decrease of DDX3 mRNA levels more than 85% leads to hepatocytes death, which must be taken into account in the process of therapy development with this target. For the characterization long non-coding RNA LL35 we used depletion by antisense oligonucleotides in vitro and in vivo. We demonstrated that LL35 RNA is downregulated in cancer hepatocytes and in the murine model of the partial hepatectomy. Analysis of the transcriptome, proteome, lipidome and metabolome in vitro and in vivo showed that LL35 is involved in the regulation of glycolysis and lipid biosynthesis in the cell. All data demonstrated that the integrated approach is necessary for the search both new targets for therapy and application of the synthetic oligonucleotides as the therapeutic agents.