Breakthrough in RNA Research Could Lead to Treatment for Neuromuscular Disorders
鈥淧othole filler鈥� molecules fit perfectly into damaged spots without disturbing healthy RNA
Heidi Opdyke
- Associate Dean of Marketing and Communications, MCS
- Email opdyke@andrew.cmu.edu
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Researchers from 麻豆村 have discovered a new 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.
鈥淭his discovery paves the way for developing highly selective, structure-based RNA therapies with fewer side effects and broader applications,鈥� said Danith Ly, professor of chemistry in the Mellon College of Science and director of the Institute for Biomolecular Design and Discovery. 鈥淲ith its precision-targeting capabilities, this approach represents a promising step toward developing effective, disease-modifying therapies for patients suffering from these debilitating genetic disorders.鈥�
Conditions like DM1 happen when certain RNA sequences repeat too many times, forming harmful structures that interfere with normal cell function. The researchers鈥� 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鈥檚 ataxia, and amyotrophic lateral sclerosis (ALS).
The research is .
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. In people without DM1, this CTG sequence is repeated between 5 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 that can trap proteins that play a vital role in RNA splicing. The trapped proteins cannot do their jobs, ultimately interfering with the production of many other proteins in cells, which, in turn, causes the symptoms of DM1. Generally, a higher number of repeats means more severe symptoms and an earlier onset.
鈥淒iseases like Myotonic dystrophy, Huntington鈥檚 disease, and fragile X syndrome, which have complicated, life-stealing symptoms, are caused by the repeat of only three nucleobases, which seems so simple,鈥� Ly said. 鈥淚f we can stop proteins from being sequestered in this hairpin, we believe we can help improve the symptoms of these diseases.鈥�
In the latest 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 target the toxic CTG repeats. The tiny ligands precisely recognize and bind to the long stretches of disease-causing RNA without disrupting healthy RNA. Ly likens them to a 鈥減othole filler鈥� that fits perfectly into the damaged spots without disturbing the rest of the road. This makes them 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.
Central to the design of Ly鈥檚 novel RNA-targeting approach are gamma peptide nucleic acids and bifacial (Janus) bases.
Ly and his colleagues in Carnegie Mellon鈥檚 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.
鈥淭hese ligands insert themselves between the two RNA strands, in contrast to the conventional antisense approach, which requires unwinding the RNA secondary and tertiary structures,鈥� 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.
Ly published 鈥淎 Pothole-Filling Strategy for Selective Targeting of rCUG-Repeats Associated with Myotonic Dystrophy Type 1鈥� in PNAS along with Carnegie Mellon graduate student Savani Thrikawala, former postdoctoral associate Shivaji Thadke, Carnegie Mellon alumni Dinithi Perera and Isha Dhami, as well as researchers at the Indian Institute of Science, Georgia State University, and Nanyang Technological University, Singapore.
Their work was funded by the National Institutes of Health, the National Science Foundation, and the DSF Charitable Foundation.
