With mRNA back in the spotlight, tRNA shows potential to treat genetic disease

Research With mRNA back in the spotlight, tRNA shows potential to treat genetic disease By Marissa Russo Aug 27, 2026 2:00pm cystic fibrosis University of Toronto genetic diseases mRNA While mRNA may be back in the headlines courtesy of Moderna and Merck & Co.'s phase 3 cancer vaccine success, new research coming out of the University of Toronto has shown that its cousin, transfer RNA (tRNA), may offer a promising therapeutic avenue for treating genetic diseases. In a study published Aug. 27 in Science, researchers who delivered inhalable modified tRNA to mice with nonsense mutation-driven cystic fibrosis noted that the therapy was safe, reached the lungs, remained there for up to 40 days and restored mutated protein function.

They also tested the efficiency of the modified tRNA against Vertex Pharmaceuticals' FDA-approved cystic fibrosis drug Trikafta in an organoid model using cells from cystic fibrosis patients. The researchers observed that treating the cells with Trikafta alone was not enough to restore protein function, and only when the cells were treated with both Trikafta and the modified tRNA was this goal achieved. The team is now working to take their inhalable tRNA into the clinic in the “next two or three years,” Bowen Li, Ph.D., associate professor at the University of Toronto’s Leslie Dan Faculty of Pharmacy, told Fierce.

“We are testing it in other disease contexts, like [Duchenne muscular dystrophy] and Rett syndrome, which lacks therapeutic options at the moment,” explained Li, who is a corresponding author of the study. In cells, messenger RNA (mRNA) provides the message for a protein to be made. This message is then read, or translated, by tRNA.

A type of mutation, called nonsense mutations, can arise during this translation process if a premature stop codon is introduced in the mRNA. As a result, the cell is left with no expression of that protein or a truncated protein, which can lead to disease. For example, nonsense mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of the causes of the inherited genetic disorder.

It causes the body to produce thick mucus and liquids that can clog up organs such as the lungs and pancreas. Li and his team sought out a way to leverage the biological reading power of tRNA to overcome the premature stop codon in cystic fibrosis. “We were able to engineer the tRNA to make sure the tRNA can still read through this premature termination codon, even though the nonsense mutation happened inside of the mRNA,” Li told Fierce.

“The tRNA can bring in amino acids to fill the hole and make sure that protein translation can still be normal.” The field of tRNA therapies still has a long way to go to catch up with the mRNA space, which experienced global success thanks to COVID-19 vaccines from Pfizer-BioNTech and as well as Moderna. Interest in mRNA was reinvigorated last week when Moderna and its partner Merck announced that their personalized mRNA cancer vaccine had successfully lengthened recurrence-free survival when paired with Keytruda in a phase 3 study of patients with high-risk skin cancer. Yet tRNA does boast some attributes that give it an advantage over mRNA.

While mRNA is very transient, Li and his team found evidence of tRNA in key epithelial cells of the lungs, which are affected in cystic fibrosis, for up to 40 days after inhalation. Additionally, mRNA therapies can carry a risk that the modified mRNA given to the cell can cause the protein target to be translated differently, Li explained. In contrast, the modified tRNA used in this study didn't introduce a foreign protein—instead it boosts the endogenous tRNA to work through the stop codon on the endogenous mRNA.

In diseases where the protein mutation is quite large, such as Duchenne muscular dystrophy, it is difficult to have high efficiency if leveraging mRNA to deliver the protein because of the size. With tRNA, the size of the protein deficiency is not a problem, because the size of the tRNA will not change, Li pointed out. “We are quickly expanding the application of the tRNA—not only limited to lung disease, but also liver disease, muscle disease and some CNS diseases such as autism,” he added.

cystic fibrosis University of Toronto genetic diseases mRNA Trikafta Biotech Research