Next-generation RNA approach provides hope for genetic diseases missed by current drugs

Researchers at the University of Toronto have created a novel RNA therapeutic strategy with the potential to treat numerous genetic diseases caused by similar disease-causing mutations. The team engineered transfer RNA (tRNA) to enable cells to bypass premature stop signals, allowing for the production of full-length proteins. This approach could lead to a new class of drugs capable of addressing a wide range of genetic diseases, including rare conditions with limited treatment options.

The study, published in Science, focuses on nonsense mutations, which introduce premature stop signals into genetic instructions for protein production. These mutations are estimated to cause about 11% of inherited genetic disorders, affecting thousands of individuals, including certain types of cystic fibrosis, muscular, and neurological diseases.

Engineered tRNA can suppress disease-causing nonsense mutations and restore full-length protein production in laboratory and preclinical models of cystic fibrosis. The approach can also be combined with existing cystic fibrosis drugs, suggesting potential for combination therapy. The researchers found that adding specific chemical tags to the engineered tRNA enhanced its activity and longevity.

Collaboration between disciplines, including chemistry and RNA biology, was crucial to the project. The researchers used lipid nanoparticles to deliver tRNA to the affected cells, a delivery system specifically designed for tRNA. This innovation is a significant advancement in tRNA therapeutics.

Cystic fibrosis, which affects the lungs and other tissues, currently has limited treatment options for roughly one in 10 patients whose disease results from nonsense mutations. The U of T researchers tested whether tRNA could restore CFTR protein function and effectiveness in these patients. The results showed that both the restored protein and the existing drug, Trikafta, were effective when used together.

This combination therapy proved successful in human airway cells with common nonsense mutations and miniature organoids derived from a cystic fibrosis patient with a complex CFTR genotype.