On January 10, 2024, a research study published in Nature by Mulroney et al. revealed that modified mRNA, commonly used in therapeutic in vitro transcribed (IVT) mRNAs, can lead to the production of frameshifted polypeptides. The incorporation of the modified ribonucleotide N1-methylpseudouridine (1-methylΨ) into mRNA was found to affect the fidelity of mRNA translation, resulting in ribosomal frameshifting.

This discovery has significant implications as it was observed that the frameshifted polypeptides elicited an off-target cellular immune response in mice and humans who were vaccinated with modified mRNA, indicating potential concerns regarding the safety and effectiveness of mRNA-based vaccines.

Therapeutic mRNA, including the clinically approved SARS-CoV-2 mRNA-based vaccines, often integrates modified ribonucleotides to enhance mRNA stability and reduce innate immunogenicity. However, the study by Mulroney et al. raises questions about the potential consequences of such modifications on mRNA translation and the subsequent immune responses.

The research highlights the need for further investigation into the impact of ribonucleotide modifications on mRNA translation and the immune responses they may elicit. This could potentially lead to advancements in the design and development of mRNA-based therapeutics and vaccines, ensuring their safety and efficacy.

The study’s findings shed light on a previously understudied aspect of mRNA biology, providing valuable insights that could influence the future development and utilization of mRNA-based treatments and vaccines.

As the field of mRNA therapeutics continues to evolve, ongoing research and scrutiny of mRNA modifications and their effects on translation and immunogenicity are crucial for advancing the understanding and application of this innovative technology.