RNA-based therapeutics: current progress and future prospects

Abstract

Recent advances of biological drugs have broadened the scope of therapeutic targets for a variety of human diseases. This holds true for dozens of RNA-based therapeutics currently under clinical investigation for diseases ranging from genetic disorders to HIV infection to various cancers. These emerging drugs, which include therapeutic ribozymes, aptamers, and small interfering RNAs (siRNAs), demonstrate the unprecedented versatility of RNA. However, RNA is inherently unstable, potentially immunogenic, and typically requires a delivery vehicle for efficient transport to the targeted cells. These issues have hindered the clinical progress of some RNA-based drugs and have contributed to mixed results in clinical testing. Nevertheless, promising results from recent clinical trials suggest that these barriers may be overcome with improved synthetic delivery carriers and chemical modifications of the RNA therapeutics. This review focuses on the clinical results of siRNA, RNA aptamer, and ribozyme therapeutics and the prospects for future successes.

Figure 1

Common chemical modifications of therapeutic nucleic acid analogs. The unmodified RNA structure is shown next to backbone (5’-phosphorothioate), LNA, and 2’-substitutions (2’-O-methoxy-ethyl, 2’-O-methyl, and 2’-fluoro).

Figure 2

Mammalian PTGS pathway for miRNAs, shRNAs, and siRNAs (A) miRNAs are transcribed from DNA as primary miRNAs (pri-miRNAs) and processed into 70-nt stem-loop precursor miRNAs (pre-miRNAs) by Drosha and DGCR8. The pre-miRNAs are transported to the cytoplasm by dsRNA-binding protein exportin 5, where they are processed into ~22 nt miRNA duplexes by the Dicer/TRBP complex. The imperfectly complementary miRNA duplexes associate with an AGO protein and are loaded into RISC, where the passenger strand is removed and the guide strand remains to target mRNA for silencing. The resulting mature RISC complex may silence gene expression either by inhibiting the initiation of translation or by transporting the complex to cytoplasmic processing bodies (p-bodies) where the mRNA is deadenylated and destroyed. (B) Like miRNAs, shRNAs are transcribed from DNA and undergo similar processing. However, the perfect Watson-Crick base-pairing between the guide strand and the target mRNA triggers AGO2-mediated cleavage of the mRNA target. (C) In contrast to shRNAs, siRNAs are artificially introduced into the cytoplasm. All steps of siRNA and shRNA are the same after processing by Dicer/TRBP.