RNA Therapy: Current Status and Future Potential

Abstract

Recent studies identified diverse RNAs including noncoding RNAs and their various action mechanisms in the cells. These RNAs regulate a variety of cellular pathways and are therefore expected to be important targets for the treatment of human diseases. Along with their extensive functional studies, RNA-based therapeutic techniques have developed considerably in recent years. After years of research and various trial and error, antisense RNAs and small interfering RNAs-based drugs have been developed and are now being used in the clinic. In addition, active research is ongoing to develop drugs based on RNA aptamer and messenger RNA. Along with the development of these RNA-based drugs, diverse strategies have been developed to transport RNA drugs into the cells efficiently. RNA therapy has many advantages over existing small molecule or monoclonal antibody-based therapies, including its potential to target all genes in the cells. This review will introduce the history of RNA therapy, and explain the basic concepts of RNA therapy and RNA-based drugs on the market or clinical trials. In addition, the future potential of RNA therapy will be discussed.

Keywords: Aptamers, Nucleotide; Nanoparticles; RNA Interference; RNA, Antisense; RNA, Small Interfering.

FIG. 1. Timeline of key discoveries in RNA therapy. See the text for details.

FIG. 2. Types of RNA therapy. (A) Antisense RNA (single-stranded RNA). The single-stranded antisense RNA is designed to bind to pre- or mature mRNA. After binding, it modulates the splicing of pre-mRNA or induces the degradation of mRNA. It can also inhibit the translation of mRNA into protein. (B) Small interfering RNA (double-stranded RNA). The small interfering RNA (siRNA) is introduced as a double-stranded form. After loading into the RNA-induced silencing complex (RISC), one strand is removed after strand separation. The siRNA-RISC complex binds to target mRNA sequence-specifically and cleaves the mRNA (depicted as scissor) inducing its degradation. (C) RNA aptamer. The RNA aptamer can bind to a specific protein and block its function. (D) Messenger RNA. After the messenger RNA (mRNA) is introduced into the cells, cellular machinery including the ribosome translates its information into a protein, the final product that can work as an enzyme or antigen.

FIG. 3. The delivery method in RNA therapy. The RNA drugs can be introduced into the cells as a naked form, although the efficiency is very low due to the high electric charge and the large size of RNAs. This problem can be solved by encapsulating the RNAs into lipid or other types of the nanoparticle. In another way, a chemical conjugate is attached to the RNA molecule, and this conjugate is recognized by a specific cell surface receptor. These nanoparticles and RNA-conjugate complexes are introduced through endocytosis and exert their effects.