March 2, 2024

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Avoiding “Off-Target” Effects: Researchers Enhance the Safety of Future mRNA Therapies

Avoiding “Off-Target” Effects: Researchers Enhance the Safety of Future mRNA Therapies



Avoiding “Off-Target” Effects: Researchers Enhance the Safety of Future mRNA Therapies

The latest research led by Professor Anne Willis, a biochemist, and Dr. James Thaventhiran, an immunologist, from the MRC Toxicology Unit at the University of Cambridge aims to ensure the safety of future mRNA therapies. Building on previous studies, their findings, published today (December 6) in the journal Nature, address concerns related to potential safety issues in mRNA-based treatments.

The researchers discovered that a chemical modification base called N1-methylpseudouridine present in current mRNA therapies is responsible for the “slippage” in mRNA sequences.

Working in collaboration with researchers from the University of Kent, the University of Oxford, and the University of Liverpool, the MRC Toxicology Unit investigated evidence of “off-target” protein production in individuals who received the Pfizer-BioNTech COVID-19 mRNA vaccine. In this study, one-third of the vaccinated individuals exhibited unexpected immune reactions, but no adverse effects were observed, aligning with extensive safety data on COVID-19 vaccines.

The research team subsequently redesigned the mRNA sequences, correcting error-prone gene sequences in the synthetic mRNA to avoid these “off-target” effects. This modification resulted in the expected protein production, offering a solution to prevent dangerous and unintended immune responses in future mRNA vaccines.

Dr. James Thaventhiran, a senior author of the report and a clinician at Addenbrooke’s Hospital, emphasized the safety of mRNA vaccines for COVID-19, stating, “The research unquestionably demonstrates that mRNA vaccination for COVID-19 is safe. Billions of doses of Moderna and Pfizer mRNA vaccines have been safely administered, saving lives worldwide.”

He added, “We need to ensure that future mRNA vaccines are equally reliable. Our demonstration of ‘anti-slippage’ mRNA is a significant contribution to the future safety of this drug platform.”

Professor Anne Willis, the director of the MRC Toxicology Unit and a senior author of the report, highlighted the importance of addressing safety concerns in the development of new mRNA therapies, stating, “These new therapies offer hope for treating various diseases. With billions of pounds flowing into the next generation of mRNA therapies, it is crucial to ensure that the design of these therapies does not result in unexpected side effects.”

Dr. Thaventhiran, who is also a practicing clinical physician at Addenbrooke’s Hospital, noted, “We can remove error-prone code from mRNA vaccines, allowing the body to produce the desired proteins, eliciting an immune response without inadvertently generating other proteins. The safety issue for future mRNA drugs lies in avoiding off-target immune responses, as misdirected immunity poses significant potential harm and should always be avoided.”

Willis added, “Our work raises concerns about this new class of drugs but also provides a solution. It is the result of important collaboration among researchers from different disciplines and backgrounds. These findings can be swiftly implemented to prevent any future safety issues, ensuring that new mRNA therapies are as safe and effective as COVID-19 vaccines.”

The use of synthetic mRNA for therapeutic purposes is appealing due to its low production cost, offering a solution to address severe health inequalities globally by making these drugs more accessible. Additionally, synthetic mRNA can be rapidly modified, for instance, to manufacture new COVID-19 variant vaccines.

In the COVID-19 vaccines developed by Moderna and Pfizer, synthetic mRNA is used to enable the body to produce spike proteins from SARS-CoV-2. The immune system recognizes the viral proteins produced by mRNA vaccines as foreign, generating protective immunity. This immunity persists, and if the body encounters the virus in the future, immune cells can act before the virus causes severe illness.

The decoding mechanism of cells, known as the ribosome, is crucial for accurately manufacturing proteins from both natural and synthetic mRNA. The precise positioning of the ribosome on mRNA is essential for producing the correct proteins because the ribosome reads three base pairs of mRNA sequence at a time. These three base pairs determine the amino acid that will be added to the protein chain next. Therefore, even a small movement of the ribosome along mRNA can severely distort the code and the resulting protein.

When the ribosome encounters a modification base called N1-methylpseudouridine in mRNA, there is approximately a 10% chance of a shift occurring, leading to mRNA misreading and the production of unexpected proteins—sufficient to trigger an immune response. Removing these N1-methylpseudouridine modifications from mRNA can prevent the production of “off-target” proteins.

Avoiding “Off-Target” Effects: Researchers Enhance the Safety of Future mRNA Therapies

Reference:
“N1-Methylpseudouridine modification of mRNA causes +1 ribosomal frameshifting,” December 6, 2023, Nature.
DOI: 10.1038/s41586-023-06800-3.

(source:internet, reference only)


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