Outlasting mRNA, tRNA restores key protein in cystic fibrosis

Clinical takeaway: A new approach may eventually reach the cystic fibrosis patients current modulators can't help, those whose disease comes from a nonsense mutation, although the work remains preclinical. 

Cystic fibrosis care changed course when CFTR modulators arrived, but a sizable minority of patients were left behind. Roughly one in 10 people with the disease carry a nonsense mutation, a premature stop signal in the gene that halts production of the CFTR protein before it is fully built. Modulators work by repairing and activating a misshapen protein. But when almost no full-length protein is made in the first place, there is nothing for them to act on, and these patients have been left without an effective option of their own. 

Transfer RNA (tRNA) is a normal part of how cells build proteins. Each one reads a bit of the genetic code and hands the cell's protein-making machinery the right building block for that spot, step by step, until the protein is complete. A suppressor tRNA is an engineered version, retooled to recognize a premature stop signal and drop an amino acid there, so the cell reads past the error and finishes the protein instead of quitting early.  

This approach is distinct from messenger RNA (mRNA) therapy, which feeds the cell a fresh set of protein instructions. A suppressor tRNA instead lets the patient's own gene be read to the end. The barriers thus far have been practical: early versions worked inefficiently, triggered immune reactions, and were difficult to deliver intact. A team took on those problems together, redesigning the tRNA and building a delivery system for it, then tested it in preclinical cystic fibrosis models. 

"No matter how powerful you make those tRNAs, without delivery, they cannot be a drug," said Jingan Chen, a PhD candidate at the University of Toronto and co-lead author of the study. "That cargo-specific delivery system is one of the major advances of our study." 

In human airway cells carrying CFTR nonsense mutations, the redesigned tRNA restored the missing protein. In cells carrying one of these mutations, it also restored the protein's function as a working channel, and the protein was still present more than 40 days later. A single chemical change to the tRNA drove much of the gain. It helped the tRNA read past stop signals more efficiently, last longer, and provoke less of the immune reaction that dogged earlier versions. 

In mice carrying a CFTR nonsense mutation, the tRNA and its delivery system together produced the largest increase in CFTR. The tRNA also outlasted mRNA: in reporter cells, the mRNA signal fell below 1% of its starting level within two weeks, while the tRNA kept working. 

The hardest test used organoids grown from one patient with a complex set of mutations who does not respond to existing drugs. Neither the tRNA nor the modulator Trikafta did much alone. Used together, they restored CFTR function. The tRNA rebuilt the full-length protein, and Trikafta acted on it. 

Beyond the lung, the same idea could work for other diseases caused by nonsense mutations, such as muscular dystrophy and some neurological disorders, because a single engineered tRNA can fix the same kind of stop-signal error wherever it shows up across different genes. The authors also raise a longer-range possibility: using tRNA to correct other kinds of mutations, not just this one. Each of those directions depends on solving delivery for each organ type. 

"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," said Bowen Li, an associate professor at the University of Toronto's Leslie Dan Faculty of Pharmacy and an affiliate scientist at the 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." 

Source: Chen J, et al. (2026 Aug 27) Science. Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis