Inhaled RNA therapy restores lung protein in cystic fibrosis models

Researchers at the University of Toronto have demonstrated that chemically modified transfer RNA molecules, delivered to the lungs via inhaled nanoparticles, can restore production of a critical protein in models of cystic fibrosis — offering a potential treatment path for patients who do not respond to existing drugs.

The study, published Thursday in Science, represents what the team calls a foundational step toward a new class of RNA-based medicines capable of addressing thousands of genetic diseases caused by a shared type of mutation.eurekalert+1

How It Works

The research targets "nonsense mutations," which insert premature stop signals into the genetic code and prevent cells from producing full-length, functional proteins. These mutations account for roughly 11% of inherited genetic disorders and affect about one in 10 cystic fibrosis patients, who cannot benefit from CFTR modulators like Vertex Pharmaceuticals' ↘ 1.07% Trikafta.genengnews+1

Led by Bowen Li, an associate professor in U of T's Leslie Dan Faculty of Pharmacy, the team engineered suppressor tRNAs that recognize premature stop codons and insert the correct amino acid, allowing cells to resume building full-length proteins. A key advance came from co-senior author Haissi Cui, who identified a single chemical modification drawn from natural tRNAs that made the engineered molecules more active and longer-lasting.utoronto

To deliver the therapy, the team developed tailored lipid nanoparticles — synthesizing about 1,000 structurally diverse lipids in a single day to find optimal candidates for tRNA delivery to the lungs.utoronto

Preclinical Results

In human airway cells carrying two common nonsense mutations, the restored CFTR protein remained functional for more than 40 days. In a patient-derived organoid model with a complex genotype containing four mutations — two of them nonsense — neither the modified tRNA nor Trikafta worked alone. But when combined, the patient's cells responded: the tRNA restored full-length protein production while Trikafta supported its folding and activity.genengnews+1

"That was a great moment for us, where we saw the potential of the therapy," said co-lead author Jingan Chen, a PhD candidate in Li's lab.utoronto

Broader Implications

Because nonsense mutations produce only three possible premature stop codons regardless of which gene is affected, the platform could theoretically address diseases of the lungs, brain, muscles, and other tissues with a common therapeutic strategy. Li's lab is already working to expand delivery to other organs.eurekalert+1

In a perspective accompanying the paper, Jacob Myerson and Drew Weissman of the University of Pennsylvania noted that "the results of Chen et al. have implications for thousands of cystic fibrosis patients," while cautioning that further work on side effects and combination therapy profiles will be needed before clinical translation.genengnews