Lessons Learned: Targeting RNA as a Therapeutic Strategy

Published on Tue, 12/11/2018

RNA Becoming a Mainstream Therapeutic Target?

The term “RNA World” has been attributed to the biochemist and Nobel laureate, Walter Gilbert, circa 1986. At the time, the reference was to a hypothetical stage in the origin of life, where proteins were not the primary implementers of the genetic code and RNA mediated the functions of early life forms. Since then, there has been nearly exponential growth in understanding of a broader RNA World—just some of the Nobel-level recognition for these discoveries include Sidney Altman and Tom Cech (1986) for work on the catalytic properties of RNA and Andrew Fire and Craig Mello (2006) for discovery of RNAi. Understanding the diversity in types and processing of RNA has yielded compelling targets for drug discovery. Perhaps the most noteworthy, recent advance is the development of the antisense oligonucleotide drug, Spinraza, which has produced dramatic improvements in SMA patients by altering splicing of the SMN2 gene. For DM1, much hope has been placed on the strategy of antisense oligo-driven RNase degradation of expanded repeat DMPK transcripts.

Targeting RNA with Small Molecule Drugs

While biologics (e.g., gene therapy, genome editing) and large molecule drugs (e.g., antisense oligos) may indeed prove successful in addressing DM, they ultimately must overcome barriers, such as bioavailability, to gain access to the multiplicity of tissue targets in the disease. Small molecule drugs represent a potentially faster track alternative to exploit RNA primary sequence, as well as secondary structure, in the discovery and development of therapies for DM.

Dr. Matt Disney and colleagues at Scripps Research Institute, Florida have published an overview of strategies to target RNA with small molecules, “Drugging the RNA World” (Disney et al., 2018). Although DM is but one of the indications discussed, the review contains important guidance for drug development in this disease.

Ribosomal RNAs (rRNA) were among the earliest RNA targets for drug development as the mechanism of action of some classes of antibacterials was linked to disruption of rRNA/tRNA interactions.

The authors describe how this early validation of RNA as a target led to designing small molecule compounds based on RNA structure—this section comprises the major thrust of the review. In an effort to target small molecules to the transcriptome, Novartis and Roche/PTC sought to impact diseases by altering splicing (e.g., SMA) or codon signals (e.g., DMD). The authors argue that increased understanding of RNA has led to an appreciation that putative RNA targets now outnumber protein targets and present a potentially more druggable environment. They also note that RNA secondary structure plays a key role both in its functionality and, via altered structure, in disease states (e.g., triplet repeat expansion disorders such as DM where altered secondary structure alters availability of RNA binding proteins).

The Disney group goes on to describe what they term as a ‘two-dimensional combinatorial screening strategy (2DCS)’ to identify small molecule compounds that can selectively target RNA. They note that current knowledge and models of RNA secondary structure are sufficient to evaluate how small molecules may interact, but that information is lacking in regard to the chemical space of targetable RNA motifs. The 2DCS strategy utilized by Disney is designed to identify ‘RNA motif-binding landscapes’ for small molecule compounds and has been successful in identifying high affinity compounds (down to low nanomolar) targeting RNA. With the 2DCS screening tool in hand, the task became matching up compounds from the screens with bioinformatics data on the structure of the intended target RNA.

The remainder of the review considers several specific examples of targeting RNA with small molecule compounds, including targeting protein binding sites in miRNAs causally linked to disease, profiling interactions between small molecules and RNA in cell models using Chem-CLIP, targeting protein binding sites in repeat expansion disorders, affecting RNA subcellular localization and function (including developing imaging techniques to assess outcomes of the approach), and targeting protein binding sites in telomerase RNA as a chemotherapeutic or in pre-mRNAs to alter splicing in FTDP or SMA. The reader gains an excellent worldview of the potential for targeting RNA-based diseases. The Disney review is but one of a series of articles on the RNA World in a recent issue of Cold Spring Harbor Perspectives in Biology.

Practical Application

Practical application of the technology discussed in the review has led to the formation of Expansion Therapeutics, seeking to develop a small molecule, RNA-targeting drug for DM1 and DM2. Understanding of RNA biology and the availability of novel strategies and tools described here is helping to optimize the efficacy and safety of drugs with the potential to reach multiple target tissues in DM patients. A plethora of DM-targeting strategies likely lies within this broad RNA World.


Drugging the RNA World.
Disney MD, Dwyer BG, Childs-Disney JL.
Cold Spring Harb Perspect Biol. 2018 Nov 1;10(11). pii: a034769. doi: 10.1101/cshperspect.a034769.