Researchers from the University of Toronto have designed a novel RNA strategy that could cure thousands of genetic disorders driven by one class of mutation. The method employed involves synthetically designed transfer RNA, or tRNA to mask cell machinery from the premature genetic stop signals and allow the cell to make full proteins.
This study, also published in Science, investigates supposedly nonsense mutations. These mutations result in an early termination codon in the genetic code cells follow to synthesize a protein. If this occurs protein synthesis may be terminated prematurely, leading to the body being left without or with very little correct protein functioning. People think around 11% of hereditary disorders are caused by nonsense mutations – it’s estimated that this figure equates to thousands of individual disorders.
The Toronto group has designed tRNA’s that ignore these premature stop codons and enable the cell to read through the genetic message. This would allow for the re-expression of a functional protein without the need to design a specific treatement for each separate mutation.
This might be interesting with rare diseases. Mutations in genes that lead to genetic disorders are numerous, numbering in the thousands, and developing a tailored drug for each individual mutation can be challenging and financially impossible. Since numerous different diseases could be the result of the three different types of premature stop codons, the same tRNA-based approach could conceivably be applied to many different genes.
Cystic fibrosis was mainly useful to develop the technique. Certain people with cystic fibrosis have nonsense mutations in their CFTR gene this may mean that they do not make a functional form of the CFTR protein. There are CFTR-modulator drugs available for many people but these tend to work when the protein is already present.
Though, in lab and preclinical models, the engineered tRNA was able to fully recover the CFTR protein. The researchers demonstrated that the recovered protein was also functional. Importantly, when they tested the use of the engineered tRNA with the existing CF drug Trikafta on airway cells taken from a cystic fibrosis patient that hadn’t been too responsive to current treatments, they observed a synergistic response that neither method was able to replicate independently:
Delivering the RNA into the right cells was a further obstaclean in-house designed lipid nanoparticle delivery vehicle was in particular created to carry the engineered tRNA to the airway tissues. Chemical modifications were used to prolong the stability and improve the activity of the engineered tRNA.
In addition, the possibilities should not be limited to only cystic fibrosis. Many genes related to muscle and neurological diseases and a handful of cancers also have nonsense mutations. As long as the mutation is natural, not artificially induced, the therapy is targeted at the mutation mechanism, rather than the disease per se, and so, its makers claim, could eventually be used as a standard treatment to many otherwise incurable diseases.
