Breakthrough in RNA Research Could Lead to Treatment for Neuromuscular Disorders

Danith Ly said this discovery paves the way for developing highly selective, structure-based RNA therapies with fewer side effects and broader applications.
Photo Credit: Courtesy of Carnegie Mellon University

Scientific Frontline: Extended "At a Glance" Summary

The Core Concept: Researchers have developed precise synthetic molecules, likened to "pothole fillers," that neutralize the toxic RNA repeats responsible for genetic neuromuscular disorders like myotonic dystrophy type 1 (DM1).

Key Distinction/Mechanism: Unlike traditional antisense therapies that require unwinding complex RNA structures to work, these ligands utilize "Janus" (bifacial) bases that insert themselves directly between RNA strands. This allows the molecule to bind to both sides of the toxic "hairpin" structure simultaneously, displacing harmful proteins without disturbing healthy RNA functions.

Origin/History: Published on January 15, 2026, by a team led by Professor Danith Ly at Carnegie Mellon University, this breakthrough builds upon years of research into peptide nucleic acids (PNAs) supported by the DSF Charitable Foundation since 2014.

Major Frameworks/Components:

• Gamma Peptide Nucleic Acids (PNAs): Synthetic molecular backbones programmed to recognize and bind to specific disease-causing genetic sequences.
• Janus Bases: Double-sided bases named after the Roman god, enabling the ligand to engage both strands of the RNA target.
• LG2b: The lead ligand identified in the study, noted for its high selectivity in displacing toxic protein-RNA complexes.
• Toxic CTG Repeats: The specific genetic "stutter" in the DMPK gene that the therapy targets to prevent cellular traffic jams.

Why It Matters: This technology represents a potential disease-modifying therapy for incurable conditions such as DM1, ALS, and Huntington’s disease. By offering higher precision and fewer side effects than current small-molecule or antisense drugs, it overcomes significant barriers in treating RNA-repeat expansion disorders.

Researchers from Carnegie Mellon University have discovered a way to target RNA that could lead to new treatment options for myotonic dystrophy type 1 (DM1), the most common adult-onset form of muscular dystrophy, and other RNA-repeat expansion disorders. 

“This discovery paves the way for developing highly selective, structure-based RNA therapies with fewer side effects and broader applications,” said Danith Ly, a professor of chemistry in the Mellon College of Science and director of the Institute for Biomolecular Design and Discovery. “With its precision-targeting capabilities, this approach represents a promising step toward developing effective, disease-modifying therapies for patients suffering from these debilitating genetic disorders.” 

What causes muscular dystrophy? 

Conditions like DM1 happen when certain RNA sequences repeat too many times, forming harmful structures that interfere with normal cell function. The researchers’ new approach provides a powerful and versatile solution for precise RNA targeting, paving the way for the development of RNA therapies with fewer side effects for disorders such as spinocerebellar ataxias, Friedreich’s ataxia and amyotrophic lateral sclerosis (ALS). 

DM1, which affects at least 1 in 2,300 people worldwide, mainly causes progressive muscle loss, weakness and myotonia, but it can also affect other parts of the body, including the heart, lungs, and eyes. There is currently no effective treatment.  

DM1 is caused by a mutation in the DMPK gene, which leads to an abnormal increase in a repeated section of genetic code, known as CTG repeats. This genetic “stutter” occurs when the body’s instructions become stuck on repeat. In people without DM1, this CTG sequence is repeated between five to 35 times. In a person with DM1, the number of repeats can be in the thousands.  

When the gene is transcribed into RNA, the chain of repeats forms a hairpin loop — a tangled structure that functions like a sticky trap for essential proteins. These proteins, which play a vital role in RNA splicing, become sequestered or trapped within the loop. The trapped proteins cannot do their jobs, creating a cellular traffic jam that interferes with the production of many other proteins in cells. Ultimately, this disruption causes the symptoms of DM1, with a higher number of repeats typically resulting in more severe symptoms and an earlier onset. 

“Diseases like myotonic dystrophy, Huntington’s disease and fragile X syndrome, which have complicated, life-stealing symptoms, are caused by the repeat of only three nucleobases, which seems so simple,” Ly said. “If we can stop proteins from being sequestered in this hairpin, we believe we can help improve the symptoms of these diseases.” 

A molecular “pothole filler” for toxic RNA 

Ly likens his team’s latest discovery to a “pothole filler” — a solution that fits neatly into damaged spots without disturbing the rest of the road. In this case, the damage is caused by toxic CTG RNA repeats. In the new research, Ly and his team, including Shivaji Thadke, a former postdoctoral associate, Dinithi Perera, a Ph.D. graduate, and Savani Thrikawala, a third-year Ph.D. student, created small, highly specific molecules called nucleic acid ligands that precisely recognize and bind to these disease-causing RNA stretches without disrupting healthy RNA. The approach is more precise and less likely to produce side effects than conventional small-molecule drugs and antisense therapies currently under development. 

Such traditional therapeutic approaches often struggle with specificity, according to Ly, either failing to distinguish between normal and pathogenic RNA or requiring complex modifications for effective delivery. The new nucleic acid ligands overcome these challenges through a bifacial recognition mechanism, which ensures precise targeting of pathogenic repeats while minimizing off-target interactions.  

Computer-generated image of a double helix with the ligand inside the helices (left) and a molecular outline of the helix.
Image Credit: Courtesy of Carnegie Mellon University

A double-sided molecular strategy 

Central to the design of Ly’s novel RNA-targeting approach are gamma peptide nucleic acids and bifacial (Janus) bases.  

Ly and his colleagues at Carnegie Mellon’s Center for Nucleic Acids Science and Technology are leaders in creating and developing peptide nucleic acids (PNAs), synthetic molecules that contain the same nucleobases as RNA and DNA. PNAs can be programmed to correspond to genetic sequences that cause disease, allowing them to hunt down and bind with detrimental sequences. In 2014, CNAST received a $3.1 million gift from the DSF Charitable Foundation to develop the next generation of PNA technology. Ly turned his focus to developing PNAs with Janus bases. Named after the two-faced Roman god, Janus PNAs are double-sided, allowing them to bind to both strands of a DNA or RNA molecule. 

“These ligands insert themselves between the two RNA strands, in contrast to the conventional antisense approach, which requires unwinding the RNA secondary and tertiary structures,” Ly said. 

In laboratory models, the lead ligand, LG2b, demonstrated remarkable selectivity for disease-causing RNA sequences, displacing harmful protein-RNA complexes without interfering with normal gene function. 

The research team is continuing to work with their ligands, optimizing them to enhance cellular uptake, refining drug delivery methods, and evaluating their efficacy in preclinical disease models.  

Funding: Their work was funded by the National Institutes of Health, the National Science Foundation, and the DSF Charitable Foundation. 

Published in journal: Proceedings of the National Academy of Sciences

Title: A pothole-filling strategy for selective targeting of rCUG-repeats associated with myotonic dystrophy type 1

Authors: J. Dinithi R. Perera, Shivaji A. Thadke, Savani W. Thrikawala, Isha Dhami, V. M. Hridya, Arnab Mukherjee, Ananya Paul, W. David Wilson, Keith W. R. Tan, Nicholas Z. W. Chan, Anh Tuân Phan, and Danith H. Ly

Source/Credit: Carnegie Mellon University | Amy Pavlak Laird

Reference Number: mbio011526_01

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