Oligonucleotides and mRNA Therapeutics

Two important classes of therapeutics based on nucleic acids are synthetic oligonucleotides and mRNA generated by in vitro transcription (IVT). Oligonucleotides are short chains of single-stranded or double-stranded nucleotides, either DNA, RNA, or a combination that are often chemically modified to improve their application as a drug substance. They are applied to modulate endogenous mechanisms of DNA and RNA processing into proteins, thereby modifying disease pathways at the genetic level rather than at the protein level like conventional drugs. In addition, messenger RNA (mRNA) encodes proteins that can be translated for therapeutic purposes, such as protein replacement therapy, gene editing, and in vaccines. Such mRNAs are much longer than oligonucleotides and have less options for chemical modification as they are synthesized enzymatically through in vitro transcription. Factors that limit the application of oligonucleotide and mRNA drugs are immunogenicity, instability, and poor pharmacokinetics. In this chapter, several mechanisms are described of how oligonucleotides/mRNAs can act as drugs, as well as several approaches to overcome the limitations that are inherent to this drug class. Recent advances include chemical modifications and formulation of oligonucleotides and mRNAs in lipid nanoparticles. These approaches have proven to be clinically successful and have led to approved antisense and siRNA drugs and mRNA vaccines.