What mRNA frameshifting means for therapeutic efficacy
Modified mRNAs have become an important platform for developing vaccines and other new therapeutic approaches. One of the most widely used modifications, N¹-methylpseudouridine (m¹Ψ), can improve protein expression while reducing unwanted immune activation, helping mRNA therapeutics produce useful levels of protein in cells.
Can N¹-Methylpseudouridine (m¹Ψ) Affect How mRNA Is Translated?
However, recent research has shown that m¹Ψ can change how ribosomes translate mRNA. Under certain sequence conditions, m¹Ψ can alter ribosome movement and, in some contexts, contribute to +1 frameshifting, potentially producing proteins that were not originally intended by the mRNA sequence. More recent work shows that these effects depend strongly on the sequence and codon context of the mRNA.
What Is mRNA Frameshifting and Why Does It Matter?
Ribosomes must move along mRNAs in particular movement patterns in order to produce the correct, intended protein. Any deviation from the correct movement pattern is called a ‘frameshift’. mRNAs containing m¹Ψ frameshift more often than normal mRNAs, and therefore produce higher levels of unintended proteins. Researchers have detected immune responses to some frameshifted protein products following mRNA vaccination in both mice and humans. However, there is currently no evidence that these findings have resulted in adverse clinical outcomes from approved mRNA vaccines.
Why Is Translation Reliability Important for mRNA Therapeutics?
For future therapeutic applications other than vaccines, translation reliability may become increasingly important. Treatments such as protein replacement therapies for hereditary diseases require higher and more prolonged protein expression compared to vaccines, and this could make unintended translation products more relevant, particularly where they could affect efficacy or safety. Understanding how modified nucleotides influence translation can therefore help researchers identify potential risks earlier in the development process.
How Can mRNA Sequence Design Improve Translation?
These findings reinforce the importance of looking beyond simple measures of mRNA expression when designing therapeutic sequences. Understanding how sequence, RNA modifications and the cellular translation machinery interact could help researchers design mRNAs that produce the right protein. At Jantomarna, we combine expertise in mRNA biology, systems biology and computational sequence design to develop mRNA sequences tailored for efficacy, safety and manufacturability.
About the author
Diala Nikolaeva is Customer Relations Manager at Jantomarna Therapeutics, where she supports the company's commercial engagement activities. Alongside her industry role, she conducts research in Business Analytics with a focus on healthcare, exploring how data-driven decision-making, strategic planning, and operational optimisation can improve healthcare delivery, identify opportunities for greater efficiency, reduce costs, and ultimately improve patient outcomes.
About the company
Jantomarna Therapeutics Limited is a private company limited by law registered in the UK with company number 16717863. Jantomarna’s mission is to harness the long-standing track records of its founders in mRNA Biology and Immunology for the design of mRNA Therapeutics with superior efficacy, patient safety, and manufacturability. We offer contract design of therapeutic sequences, co-development of therapeutics, and licensing of our design software. If you are interested in mRNA Therapeutics design contact us at info@jantomarna.co.uk .