In recent years, the question of whether RNA can serve as a viable therapeutic target has become one of the most exciting debates in life sciences and drug discovery. Traditionally, drug development has focused on proteins as the primary molecular targets. However, with advances in genomics and the unprecedented success of RNA vaccines, the spotlight has shifted to RNA itself as a direct target for therapy.
RNA is far more than just a messenger carrying genetic information from DNA to proteins. As a molecule, RNA folds into diverse secondary and tertiary structures that dynamically influence translation, splicing, and stability. In essence, RNA is not only information, but also structure and function combined. If we can therapeutically manipulate these properties, we may open new treatment opportunities for diseases that have remained intractable until now.
In this article, I will explain the scientific foundations of RNA secondary structures, their connections to diseases, examples of successful therapies, stories of withdrawal or failure, the current activities of biotech companies, and the contributions and limitations of in silico approaches. I will conclude with my own perspective on the future of RNA-based therapeutics.
The Scientific Basis of Targeting RNA
RNA Secondary Structures as Functional Switches
RNA molecules form various secondary structures through base pairing: hairpins, stem-loops, and pseudoknots. These are not simply shapes, but functional “switches” that regulate molecular processes.
For instance, a hairpin in the 5’UTR of an mRNA may block ribosome binding. When environmental conditions change — such as temperature or metabolic state — the hairpin may melt, allowing translation to initiate. This makes RNA a dynamic regulator that can respond to physiological cues, rather than a static code.
Connections to Human Diseases
Accumulating research has shown that abnormal RNA structures can directly contribute to disease pathogenesis:
- Cancer: The IRES element in MYC mRNA forms stable stem-loops that enhance translation. Disrupting these structures may suppress tumor growth. Similarly, misfolding of telomerase RNA (TERC) is implicated in both cancer and aging.
- Neurodegenerative diseases: Expanded C9orf72 repeats form abnormal hairpins and G-quadruplexes that drive ALS and frontotemporal dementia. Fragile X syndrome is linked to CGG repeat hairpins in the FMR1 gene.
- Infectious diseases: The SARS-CoV-2 frameshift element (FSE), a pseudoknot, is critical for viral replication. Targeting this structure was considered a promising antiviral approach.
Successful Examples
Antibiotics: Classical RNA Structural Drugs
RNA-targeting drugs are not entirely new. Macrolides, aminoglycosides, and tetracyclines all bind to rRNA structural motifs in the ribosome and block translation. These have been in clinical use for decades, representing the earliest proven examples of RNA-targeted therapeutics.
Spinraza: A Breakthrough in SMA Therapy
Spinraza (nusinersen, developed by Biogen/Ionis) is a groundbreaking treatment for spinal muscular atrophy (SMA). SMA arises from the loss of the SMN1 gene, but humans have a paralog, SMN2. Unfortunately, due to an intronic hairpin structure, exon 7 is frequently skipped, preventing full-length protein production. Spinraza is an antisense oligonucleotide (ASO) that disrupts this hairpin, correcting splicing. It is the first clear clinical success of directly targeting RNA secondary structure for therapeutic purposes.
RNA Vaccines and siRNA Therapeutics
The success of mRNA vaccines during the COVID-19 pandemic also owes much to RNA structural biology. By optimizing codon usage and 5’UTR folding, developers enhanced both stability and translational efficiency. Alnylam’s Onpattro (patisiran), the first approved siRNA drug, works by degrading target mRNA directly. Together, these therapies prove RNA can be engineered into powerful therapeutic modalities.
Withdrawals and Setbacks
Despite these successes, directly targeting RNA secondary structures with small molecules has been highly challenging. Unlike proteins, RNA lacks stable hydrophobic pockets, and its conformations are highly dynamic.
Merck significantly downsized its RNA-targeted drug discovery programs, while Novartis also scaled back RNA biology initiatives. Among biotechs, Ribometrix once partnered with Pfizer but later reduced programs due to insufficient progress. Arrakis Therapeutics garnered tremendous excitement, yet clinical entry remains elusive. These experiences highlight the gap between investor expectations and scientific realities.
Current Frontiers
- Infectious disease: Efforts at MIT and Stanford explored ASOs and small molecules against the SARS-CoV-2 frameshift element.
- Cancer: lncRNAs such as MALAT1 and HOTAIR are emerging structural targets. The MYC IRES remains a high-profile candidate.
- Biotechs: Arrakis Therapeutics continues to pursue RNA-targeted small molecules, Storm Therapeutics focuses on RNA modifications and structure, and Skyhawk Therapeutics develops splicing-modulating ASOs.
Contributions and Limits of In Silico Approaches
Contributions
Computational predictions support early RNA drug discovery in multiple ways. Algorithms such as RNAfold predict secondary structures, while Boltzmann ensemble methods estimate conformational probabilities. AI models are being trained to assess the structural impacts of disease mutations. Virtual screening enables identification of small molecules that may fit into transient RNA pockets among millions of compounds.
Limits
However, RNA is inherently dynamic. Within the cell, its structures are constantly influenced by proteins, ions, and ATP-driven remodeling. Static computational models cannot fully capture these complexities. Therefore, experimental probing — such as SHAPE chemistry and high-throughput structure mapping — remains essential for validating predictions.
Future Outlook
I see three major directions for the future of RNA-targeted therapeutics. First, following the success of ASOs and siRNAs, we will witness a second wave of small molecules designed to directly target RNA structures. Second, RNA structural changes will emerge as diagnostic biomarkers, enabling more personalized medicine. Third, integration of AI predictions with experimental probing will finally allow us to capture the “living dynamics” of RNA in cells.
My Perspective
For decades, RNA was considered unstable and “undruggable.” I believe the opposite: its flexibility and structural diversity make it a uniquely powerful therapeutic target. The successes of Spinraza and mRNA vaccines prove RNA can be harnessed for real-world medicine. While setbacks highlight the challenges, I am convinced RNA structural therapeutics will open entirely new paths in drug discovery.
RNA remains an untapped frontier. Progress will take time, with inevitable failures along the way, but the rewards are immense. I firmly expect that targeting RNA structures will become one of the key pillars in conquering human disease.
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This article was edited by the Morningglorysciences team
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