Since the milestone discoveries of catalytic RNAs in the early 1980s and RNA interference in the late 1990s, the biological understanding of RNA has evolved from simply an intermediate between DNA and protein to a dynamic and versatile molecule that regulates the functions of genes and cells in all living organisms. These and similar breakthroughs have led to the emergence of numerous types of RNA-based therapeutics that broaden the range of “drug-able” targets beyond the scope of existing pharmacological drugs. RNA-based therapeutics can be classified by the mechanism of activity, and include inhibitors of mRNA translation (antisense), the agents of RNA interference (RNAi), catalytically active RNA molecules (ribozymes), and RNAs that bind proteins and other molecular ligands (aptamers).
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.
Despite a number of hurdles encountered along the way, more than 50 RNA or RNA-derived therapeutics have reached clinical testing. Challenges with the delivery, specificity, stability, and immune activation of RNA therapeutics have spawned improvements in synthetic and natural nucleic acid carriers and the development of chemically modified oligonucleotides. In this review, we will discuss many of these refinements and highlight several promising therapeutics currently in the clinic.