Researchers at the University of Toronto have developed a next-generation RNA therapeutic approach with the potential to treat a wide range of genetic diseases that share certain disease-causing mutations. The work advances an emerging platform in genetic medicine centred on transfer RNA, or tRNA. The team engineered tRNA to help cells read through premature stop signals and complete production of full-length proteins that would otherwise be truncated or absent.

Study lead Bowen Li, an associate professor in U of T’s Leslie Dan Faculty of Pharmacy, says the research could lay the foundation for a new class of drugs designed to treat a swath of genetic diseases through a common therapeutic strategy.

“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 with few treatment options.

Li and his team focused on “nonsense mutations,” which introduce premature stop signals in genetic instructions for protein production. Although nonsense mutations cause only about 11 percent of inherited genetic disorders, those number in the thousands, including subsets of cystic fibrosis and certain muscular and neurological diseases.

The study, published in Science on August 27, demonstrates that engineered tRNA can suppress disease-causing nonsense mutations and restore full-length protein production across laboratory and preclinical models of cystic fibrosis. The approach can be combined with existing cystic fibrosis drugs, suggesting potential for combination therapy.

“The same type of premature stop signal can occur in many different genes, causing diseases that affect the lungs, brain, muscles and other tissues. 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.”

Study co-lead Haissi Cui, assistant professor of chemistry in the Faculty of Arts & Science, directed the team toward adding chemical tags found in natural tRNAs. This modification increased the engineered tRNA’s activity and longevity.

“Interdisciplinary collaboration was key to this project. We used nature as our design guide and found that adding one specific modification made the engineered tRNA more active and longer-lasting.”

Jingan (Charles) Chen, a researcher in Li’s lab and co-lead author, addressed the challenge of delivering tRNAs to target cells using lipid nanoparticles—the fatty delivery vehicles used in COVID-19 vaccines, but redesigned for tRNA transport.

“No matter how powerful you make those tRNAs, without delivery, they cannot be a drug. That cargo-specific delivery system is one of the major advances of our study.”

In recent years, cystic fibrosis treatment has been transformed by drugs called CFTR modulators, such as Trikafta. However, these are ineffective for approximately one in ten patients whose disease stems from nonsense mutations. Modulators repair misshapen CFTR proteins but cannot replace proteins never produced.

The U of T researchers tested whether tRNA could address this gap. In human airway cells with two common nonsense mutations, the CFTR protein reappeared and functioned properly, remaining active for over 40 days. Further preclinical tests confirmed these results.

Research team members Jim Hu and Tanja Gonska, both SickKids scientists with U of T appointments, provided access to tissue from a cystic fibrosis patient with a complex CFTR genotype containing four mutations—two nonsense mutations—that left them unresponsive to existing drugs. Patient cells grown into organoids showed limited response to modified tRNA or Trikafta alone but responded when both were used together, with tRNA restoring full-length protein production.

Lisa Dolovich, dean of the Leslie Dan Faculty of Pharmacy, views this study as part of U of T’s tradition of developing treatments from the body’s own biology, from insulin to GLP-1 discoveries behind drugs like Ozempic.

“This is the kind of foundational research that medical breakthroughs are built on. By tackling the science and the delivery together, we’re closer to turning a discovery into a drug.”

The researchers indicate this study represents a significant advance in demonstrating tRNA’s therapeutic promise. Li’s lab plans to expand the approach to other organs, each requiring specialized delivery systems. For lung applications, the team has demonstrated that particles can survive aerosolization—a first step toward an inhalable home treatment.

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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Journal: Science
DOI: 10.1126/science.aeb0054
Article Title: RNA breakthrough provides hope for thousands of untreatable diseases
Publication Date: August 27, 2026

Source: University of Toronto