A small chemical change to messenger RNA could help future vaccines and medicines produce more therapeutic proteins inside cells, according to researchers at Johns Hopkins Medicine.
Scientists have identified a potential alternative to the RNA modification widely used in current mRNA technology. Their research suggests that replacing N1-methylpseudouridine, known as m1Ψ, with a naturally occurring modification called N4-acetylcytidine, or ac4C, could increase the speed at which cells translate mRNA into proteins.
The findings were published in the journal Nature and could eventually have implications for vaccines and treatments being developed for infectious diseases, cancer and autoimmune conditions.
The current leading mRNA platform uses m1Ψ, which became widely known through the COVID-19 vaccines. Researchers are now investigating the technology for a much broader range of medical applications.
The Johns Hopkins team compared the two modifications in cultured human dendritic cells and mouse liver cells. They found that ribosomes, the structures responsible for reading mRNA and producing proteins, moved considerably faster along ac4C-modified mRNA.
“Our results show that ac4C causes cells to produce more therapeutic proteins than the industry standard mRNA platform,” said Bin Wu, an associate professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.
The researchers found that ribosomes travelled almost twice as fast on ac4C-modified mRNA compared with m1Ψ-modified mRNA.
Wu compared the difference to traffic congestion. When ribosomes move more slowly, they can build up along an mRNA strand and create what researchers describe as a molecular traffic jam. Faster movement could allow more ribosomes to process the same strand efficiently, increasing protein production.
The potential benefit could be significant for mRNA medicines. These treatments work by giving cells temporary genetic instructions to produce specific proteins. The amount of protein generated can influence whether a treatment reaches the level needed to produce a therapeutic effect.
If ac4C allows cells to produce more protein from the same amount of mRNA, future therapies could potentially require smaller doses. That could reduce the amount of material needed for some treatments while improving their effectiveness.
Researchers point out that more than 170 RNA modifications are known to exist, but only a limited number have been extensively investigated for use in mRNA therapies.
The discovery could open another area of research as scientists seek to improve the performance of mRNA technology. Potential applications include vaccines against infectious diseases, cancer treatments that activate immune responses and therapies designed to modify immune activity in autoimmune disorders.
However, ac4C is still at an experimental stage. The findings have so far been demonstrated in laboratory and animal cells, meaning further studies will be needed to determine whether the modification is safe and effective in living organisms.
If future research confirms the results, the chemical change could become an important step in improving the next generation of mRNA-based medicines.
