Tapping the RNA world for therapeutics

Abstract

A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

“…RNA interference (RNAi) is a prominent and natural cellular process for understanding gene function in many cell types . Taking advantage of this process, specific genes can be downregulated by intracellular delivery of synthetic small interfering RNA (siRNA) and micro RNA (miRNA) molecules .…”

Targeting RNA: A Transformative Therapeutic Strategy

“…Landmark events, such as the discovery of the helical structure of DNA and the completion of the human genome project, led to the development of oligonucleotide medicines in the postgenomic era ( Figure ). It has been postulated and generally recognized that only one‐third of the roughly 20,000 proteins in the human genome are druggable by small molecules and protein‐based drugs (e.g., monoclonal antibodies . This leaves a large gap in treating human disease, and this gap, in part, could be filled by therapeutic oligonucleotides.…”

“…In principle, oligonucleotides can be rationally designed against virtually any genetic target . Their unique mechanism of action differentiates this class of therapeutics from small molecules and protein therapeutics ( Table ) . Oligonucleotides bind to their cognate RNA target by Watson‐Crick hybridization with high selectivity and affinity.…”

“…In addition, clustered regularly interspaced short palindromic repeats‐Cas technology utilizes the antisense pairing of a single guide RNA to a specific DNA target site to directly edit genomic DNA . As a result, the functional output of the DNA sequences within the endogenous genome can be modified as a means to cure genetic disease …”

“…The concept of a synthetic oligonucleotide to control the expression of selected genes was first demonstrated 4 decades ago by Stephenson and Zamecnik . Since then, it has been recognized that oligonucleotide therapeutics can be highly specific and can target disease‐relevant proteins or genes that are inaccessible by small molecules and proteins . However, the anticipated clinical success was not achieved until recently after innovation and technology breakthroughs overcame some of the major hurdles of these therapeutics .…”