Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine

SIMPLE SUMMARY: RNA-based drugs are an attractive approach for personalized treatment of cancer and other diseases. This review focuses on two related classes of short non-coding RNA: microRNAs (miRNAs) and small interfering RNAs (siRNAs). miRNAs are endogenous short RNAs that bind multiple messenger RNAs (mRNAs) and prevent the production of their gene-products, whereas siRNAs are exogenous RNAs that target a single and specific mRNA for degradation. This review describes the development, challenges, and clinical successes of short RNA-based drugs. We provide several examples of how these RNA drugs are designed, chemically modified and delivered for treatment of different cancer types, cardiovascular disease, and rare genetic disorders. We highlight the similarities, differences, and considerations to maximize the treatment efficacy of miRNA-based vs. siRNA-based drugs. ABSTRACT: Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine.