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 centered 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, Associate Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, said that 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.

Li said, “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. 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.”

Li and his team homed in on nonsense mutations. These mutations introduce a premature stop signal into the genetic instructions for making a protein. The result: Cells may produce little or no full-length functional protein, disrupting vital functions in ways that are difficult to treat.

Although nonsense mutations are estimated to cause only about 11 per cent 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 Aug. 27, shows that tRNA can be engineered to suppress disease-causing nonsense mutations and restore full-length protein production across a series of laboratory and preclinical models of cystic fibrosis. The researchers also found that the approach can be combined with existing cystic fibrosis drugs, suggesting the potential for combination therapy.

The work is still early, but could have far-reaching applications, says Li. While nonsense mutations occur in many different genes and cause many different diseases, they arise from only 3 possible premature stop signals.

Li further said, “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 recognise these shared stop signals, so that one therapeutic strategy could potentially be applied across many different genetic diseases.”