Non-coding RNAs as drug targets

Abstract

Most of the human genome encodes RNA that does not code for protein. These noncoding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs targeting ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during development of technologies to target mRNA. Here, we will discuss the growing field of ncRNA – including microRNA, intronic RNA, repetitive RNA and long non-coding RNA - and assess the potential and challenges in their therapeutic exploitation.

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

“…Examples are (in addition to delivery) potential issues of removal of complexed DNA by phagocytic immune cells from the bloodstream, off-target effects and resulting toxicity such as cytokine release syndrome and hematological toxicity such as thrombocytopenia and biological stability of these agents in biological fluids and tissues (179)(180)(181)(182)(183). The detailed discussion of these issues is not in the scope of this review.…”

“…Other miR-inhibitory agents are antimiR-MASK single-strand ASOs which are complementary to the miR-binding nucleotides in the 3'-UTR of the target RNA. Or miR sponges that harbor multiple (4 to 16) seed binding sites as decoys and duplex RNAs which induce degradation due to RNA interference (RNAi) and hairpin RNAs, which mediate miR degradation (179)(180)(181)(182)(183). Finally, small molecule inhibitors may be able to prevent binding of miRs to 3'-UTR seed sequences.…”

“…Further modifications may include 5' o 3' additions of entities to enhance tissue targeting (e.g. cholesterol (179)(180)(181)(182)(183). Other miR-inhibitory agents are antimiR-MASK single-strand ASOs which are complementary to the miR-binding nucleotides in the 3'-UTR of the target RNA.…”

Long Non-coding RNAs and their Role in Metastasis

“…An additional mode of intervention is to block the interaction of lncRNA with proteins mediated by domain-domain interactions involved in epi-genetic or translational control. Decoy RNAs derived by systemic evolution of ligands by experimental enrichment (SELEX) (169,170) or small molecules competing for domain-domain interaction by mimicry of the secondary structure of bindng partners are candidates for disrupting domain-domain interactions (165,171,172). Another option is inactivation of lncRNA structure due to blocking of correct folding (171).…”

“…Selection for therapeutic targets will be based on data including identification of tumor types with deregulated expression, abundance of expression and cellular localization. In addition, MOA studies such as identification of interacting partners such as DNA, RNA or protein, in vitro and in vivo metastasisrelated assays and efficacy studies as well as correlation of expression with metastatic risk and survival in patients will all be important for target identification (161)(162)(163)(164)(165). In case of down-regulated metastasis-suppressing lncRNAs, substitution therapy with liposomes or nanoparticles delivering plasmidbased expression vectors or expression of the corresponding lncRNA with viral vectors are options for interference.…”