Nucleic Acid Therapeutics

In past decades, small molecules and therapeutic antibodies dominated the field of therapeutic development. Nucleic acids have now enabled new classes of therapeutics in diverse ways, with some 20 nucleic acid therapeutics approved and hundreds more in clinical trials. Oligonucleotides can silence gene expression by recruiting RNase H or RNA interference (RNAi) machinery and when designed to target splice sites, or splice signals within pre-mRNA, oligonucleotides can modulate splicing. Activation of gene expression can be achieved through multiple mechanisms, all of which are at an earlier stage of development than gene silencing and splice switching. A full gene can be delivered to cells using a viral vector, which can be used to provide a durable replacement copy of a defective gene or for introduction of a new function. The delivery of a modified mRNA allows transient replacement of a defective gene or introduction of a sequence only transiently needed, such as an encoded antigen. Finally, delivery of an RNA-guided clustered, regularly interspersed, short palindromic repeats (CRISPR) protein, or the RNA or DNA which encodes that protein, can be used to create permanent edits in cellular DNA. In all of these cases, platform technologies, including optimized approaches to chemical modification, have taken years or decades to develop. Nonetheless, each success informs and enables the development of new drugs, built on the same platform, but with a different sequence, and to target a different disease. The ability to use existing platform technologies and rationally-designed sequences has enabled the development of drugs for rare diseases, and even for a solo patient.