Researchers alter mRNA therapies for safer immune responses

N1-methylpseudouridylation induces +1 ribosomal frameshifting in mRNA.

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Researchers found that when cells misinterpret therapeutic mRNA, it can cause an unexpected immune response. They pinpointed the specific sequence in the mRNA responsible for this and figured out how to prevent unintended immune reactions. This discovery is crucial for making future mRNA treatments safer. As large amounts of money are invested in new mRNA therapies, ensuring they are designed to be secure and free from unintended side effects is essential. 

mRNA, ‘messenger ribonucleic acid,’ is the genetic material guiding cells to create specific proteins. Researchers from the Medical Research Council Toxicology Unit found that the cellular machinery reading mRNA can make mistakes, especially when encountering certain chemical modifications common in mRNA therapies. These mistakes result in the production of unintended proteins, causing an unwanted immune response.

mRNA vaccines are a big deal. They’ve been vital in controlling COVID-19, and now they’re being looked at for treating cancers, heart issues, respiratory problems, and more.

This breakthrough in treatment comes from the work of scientists Katalin Karikó and Drew Weissman. They found that by tweaking the building blocks of mRNA, these synthetic mRNAs can sneak past our body’s defenses and get into cells to do their job. This discovery earned them the Nobel Prize in 2023.

Researchers like Professor Anne Willis and Dr. James Thaventhiran from the University of Cambridge are building on this progress. They’re making sure that future mRNA therapies are safe. Their recent report in the journal Nature highlights that certain chemical modifications in mRNA, like N1-methyl pseudouridine, can cause ‘slips’ in the mRNA sequence. Understanding this helps prevent safety issues in upcoming mRNA treatments.

In partnership with researchers from the Universities of Kent, Oxford, and Liverpool, the MRC Toxicology Unit team looked into the mRNA Pfizer COVID-19 vaccine. They checked if it caused unintended immune responses by testing for ‘off-target’ proteins. Out of 21 vaccinated patients, about one-third had this response. However, it didn’t cause any harm, matching the known safety of these vaccines.

The team then fixed the genetic sequences in the synthetic mRNA to prevent these unintended effects. By doing this, they made sure the vaccines produced the suitable protein without triggering unwanted immune responses. These design changes can be easily applied to future mRNA vaccines to make them effective while avoiding risks.

Dr James Thaventhiran from the MRC Toxicology Unit, a report’s senior author, said, “Research has shown beyond doubt that mRNA vaccination against COVID-19 is safe. Billions of Moderna and Pfizer mRNA vaccine doses have been safely delivered, saving lives worldwide.”

He added: “We need to ensure that mRNA vaccines of the future are as reliable. Our demonstration of ‘slip-resistant’ mRNAs is a vital contribution to the future safety of this medicine platform.”

“These new therapeutics hold much promise for treating many diseases. As billions of pounds flow into the next set of mRNA treatments, it is essential that these therapeutics are designed to be free from unintended side effects,” said Professor Anne Willis, Director of the MRC Toxicology Unit and joint senior author of the report.

Dr. Thaventhiran, who also works at Addenbrooke’s hospital, explained that “we can fix the mistakes in mRNA vaccines to ensure our body produces the suitable proteins for a robust immune response. This prevents the unintended creation of other proteins, which could be harmful. Avoiding off-target immune responses is crucial for the safety of future mRNA medicines.”

Professor Willis added that their work identifies a problem and provides a solution. Collaboration between different researchers was essential. These findings can be quickly applied to prevent safety issues in the future and ensure new mRNA therapies are as safe and effective as COVID-19 vaccines.

Using synthetic mRNA for treatments is appealing because it’s cost-effective and can address health inequalities worldwide. Additionally, it allows for quick adjustments, like creating a new vaccine for a different COVID-19 variant.

The Moderna and Pfizer COVID-19 vaccines use synthetic mRNA to instruct the body to make the spike protein from the virus. This helps the body recognize and defend against the virus, providing lasting immunity. The cell’s decoding machinery, a ribosome, reads the genetic code of mRNA to produce proteins. Precise ribosome positioning is crucial, as even a tiny shift can distort the code and result in the wrong protein.

In the case of mRNA vaccines, the presence of modified bases, specifically N1-methyl pseudouridine, causes the ribosome to slip around 10% of the time. This leads to misreading mRNA and producing unintended proteins, triggering an immune response. Removing these modified bases prevents the production of unintended proteins. The Research, funded by the Medical Research Council and the Wellcome LEAP R3 program, was supported by the NIHR Cambridge BRC.

In conclusion, researchers are actively reengineering future mRNA therapeutics to eliminate the risk of harmful immune responses.

Journal reference:

  1. Mulroney, T.E., Pöyry, T., Yam-Puc, J.C. et al. N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting. Nature. DOI: 10.1038/s41586-023-06800-3.

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