This new approach targets disorders including cystic fibrosis, muscular dystrophy, and some cancers.
In lab-grown tissue from a cystic fibrosis patient who did not respond to existing drugs, researchers restored production of a full-length protein and gave Trikafta something it could act on. The patient’s cells responded when the drug was combined with engineered transfer RNA, or tRNA, even though neither treatment did much on its own.
The University of Toronto team designed the tRNA to bypass mutations that tell cells to stop making a protein too soon. Because the same type of premature stop signal can occur in many different genes, the researchers hope the strategy could eventually be applied across multiple genetic diseases rather than developing a separate therapy for every individual mutation.
Published in Science, the study showed that engineered tRNA could suppress these disease-causing mutations and restore full-length protein production across laboratory and preclinical models of cystic fibrosis.
Patient cells point to combination therapy
One experiment used tissue from a cystic fibrosis patient with a complex CFTR genotype containing four mutations, two of them nonsense mutations. The patient was unresponsive to existing drugs. Research team members Jim Hu and Tanja Gonska, both SickKids scientists with appointments in U of T’s Temerty Faculty of Medicine, provided access to the tissue.
The samples were grown into organoids, miniature models made from patient tissue. Modified tRNA alone had little effect, and neither did the cystic fibrosis drug Trikafta. When the two were combined, however, the cells responded. The tRNA restored production of the full-length protein, giving Trikafta something to work with.
Cystic fibrosis puts the strategy to test
The researchers also tested whether engineered tRNA could restore a CFTR protein that actually worked. In human airway cells carrying two common nonsense mutations, the protein returned, functioned as it should, and remained present for more than 40 days. Further preclinical tests pointed in the same direction.
Study lead Bowen Li, an associate professor in U of T’s Leslie Dan Faculty of Pharmacy, says the broader goal is to develop a common strategy for diseases that share this type of mutation.
“There are so many types of disease-causing mutations – many affecting only a small number of people – that developing a separate gene therapy for every individual mutation is extremely challenging,” says Li, who is also an affiliate scientist at the University Health Network’s Princess Margaret Cancer Centre.
“With tRNA therapeutics, our goal is to develop a common therapeutic approach that could potentially address the same type of mutation across many different genes and diseases, including rare conditions that currently have few or no effective treatment options.”
Nonsense mutations create a common target
The approach focuses on “nonsense mutations,” which introduce a premature stop signal into the genetic instructions for making a protein. This can leave cells with little or no full-length functional protein, disrupting vital functions.
Nonsense mutations are estimated to cause about 11 percent of inherited genetic disorders. Those disorders number in the thousands and include subsets of cystic fibrosis as well as certain muscular and neurological diseases.
“The same type of premature stop signal can occur in many different genes, causing diseases that affect the lungs, brain, muscles and other tissues”, says Li. “Our long-term goal is to develop tRNA medicines that recognize these shared stop signals, so that one therapeutic strategy could potentially be applied across many different genetic diseases.”
For the approach to work as a potential medicine, the researchers had to make the engineered tRNA more effective and find a way to deliver it to the cells that needed it.
Chemical tuning and delivery solve key hurdles
Study co-lead Haissi Cui, assistant professor of chemistry in the Faculty of Arts & Science, pointed the team toward chemical tags found naturally on tRNAs. Adding one specific modification made the engineered tRNA more active and longer-lasting.
“Interdisciplinary collaboration was key to this project,” says Cui. “We used nature as our design guide and found that adding one specific modification made the engineered tRNA more active and longer-lasting. It shows what becomes possible when chemistry and RNA biology come together.”
The team also needed a way to deliver the tRNA into cells. Jingan (Charles) Chen, a researcher in Li’s lab and co-lead author of the study, worked on this challenge. The researchers used lipid nanoparticles, the fatty bubbles that carried mRNA in the COVID-19 vaccines, but redesigned them to deliver tRNA.
“No matter how powerful you make those tRNAs, without delivery, they cannot be a drug,” says Chen, a PhD candidate in the Leslie Dan Faculty of Pharmacy and the Institute of Biomedical Engineering.
“That cargo-specific delivery system is one of the major advances of our study. We used a tailored lipid nanoparticle delivery system that is specifically developed for tRNA.”
Lisa Dolovich, dean of the Leslie Dan Faculty of Pharmacy, sees the study as part of U of T’s tradition of drawing from the body’s own biology to develop treatments, from insulin to the GLP-1 discoveries behind drugs like Ozempic.
“This is the kind of foundational research that medical breakthroughs are built on,” Dolovich says. “By tackling the science and the delivery together, we’re closer to turning a discovery into a drug.”
Reference: “Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis” by Jingan Chen, Muye Zhou, Songtao Dong, Fanglin Gong, Rasangi Tennakoon, Breanna Y. Seto, Ziyan Rachel Chen, Zhichang Peter Zhou, Jingyi Pan, Yue Xu, Sijin Luozhong, Colette Maya Macarios, Santiago Tijaro-Bulla, Tanja Gonska, Jim Hu, Haissi Cui and Bowen Li, 27 August 2026, Science.
DOI: 10.1126/science.aeb0054
The research was supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council, Cystic Fibrosis Canada, the Cystic Fibrosis Foundation, the New Frontiers in Research Fund, the Canada Research Chairs Program, the Connaught Fund, the Harrington Discovery Institute and the National Institutes of Health.
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