Biological and Therapeutic Applications of Small RNAs

Abstract

In the past decade, small RNAs including small interfering RNA (siRNA) and microRNA (miRNA) have attracted intense interest due to their unique roles in fundamental biological processes by regulating the stabilities and functions of mRNAs. As illustrated in Fig. 1, the numbers of publications related to siRNA and miRNA have increased dramatically in recent years. Although miRNA was discovered earlier than siRNA, its importance was not fully realized as siRNA from 2000 to 2005. However, while the siRNA publications reached a plateau after 2007, the number of publications on miRNA has increased exponentially since 2005. siRNAs are artificial double-stranded RNAs of 21–23 nt in length, while miRNAs are endogenous singlestranded RNAs of 21–25 nt. Both siRNA and miRNA are non-coding RNAs that post-transcriptionally suppress gene expressions by binding to their complementary mRNAs. The major difference between siRNA and miRNA is that each siRNA only specifically targets a single mRNA and induces its degradation, while a single miRNA targets hundreds of mRNAs either by blocking protein translation or destabilizing the mRNA molecules. This difference comes from the fact that siRNA always forms a perfect match to its complementary mRNA, while miRNA only forms imperfect matches to its multiple mRNA targets (1–3). This theme issue focuses on recent advances in the biological and therapeutic applications of siRNA and miRNA. There are six articles in this issue highlighting research from studying gene functions to delivery to therapeutic application of siRNA. Since its discovery, siRNA has been widely applied as a powerful tool to study genetic functions of a specific gene. To further expand the applications of siRNA in gene function studies, Friedman et al. describe a novel light-activated RNA interference (RNAi) strategy by incorporating photolabile groups (di-methoxy nitro phenyl ethyl or DMNPE) to multiple double-stranded precursors of siRNA (dsRNA). Phosphorothioate linkages are also incorporated to increase the serum stability of the dsRNA. This strategy allows the control of the spacing, timing, and amount of gene expressions by adjusting light exposure. A successful light-controllable RNAi is particularly useful for the study of developmental biology or targeted delivery to specific sites in the body. Another promising application of siRNA is the treatment of various diseases by silencing their key modulators. Currently, there are 13 ongoing clinical trials using siRNA for numerous diseases. A review by Schaffer et al. discusses basic action mechanisms and therapeutic applications of RNAi in antiviral therapy. Design considerations, delivery strategies, computational insight, and areas for future improvement are described. Another article by Nemunaitis and colleagues summarizes the potentials, challenges, and current status of small RNA-based cancer therapies. As an example of developing siRNA therapy, Cheng’s group explore the potential therapeutic application of PCBP2 siRNA in treating alcoholic liver fibrosis which is characK. Cheng (*) Division of Pharmaceutical Sciences, School of Pharmacy University of Missouri—Kansas City 2464 Charlotte Street, HSB 5250 Kansas City, Missouri 64108-2718, USA e-mail: chengkun@umkc.edu