Researchers at the University of Cambridge have discovered that misreading of therapeutic mRNAs by the cell’s decoding machinery can cause an unintended immune response in the body.
The researchers have identified the sequence within the mRNA that causes this to occur and found a way to prevent ‘off-target’ immune responses to enable the safer design of future mRNA therapeutics.
Dr James Thaventhiran from the MRC Toxicology Unit said: “Research has shown beyond doubt that mRNA vaccination against COVID-19 is safe.
“Billions of doses of the Moderna and Pfizer mRNA vaccines have been safely delivered, saving lives worldwide.
“We need to ensure that mRNA vaccines of the future are as reliable.
“Our demonstration of ‘slip-resistant’ mRNAs is a vital contribution to future safety of this medicine platform.”
The researchers discovered that the cellular machinery that ‘reads’ mRNAs ‘slips’ when confronted with repeats of a chemical modification commonly found in mRNA therapeutics.
In addition to the target protein, these slips lead to the production of ‘off-target’ proteins, triggering an unintended immune response.
mRNA vaccines have been used to control the COVID-19 pandemic and are already proposed to treat various cancers, cardiovascular, respiratory, and immunological diseases in the future.
The latest developments build on previous advances to ensure the prevention of any safety issues linked with future mRNA-based therapeutics.
The researchers identified that bases with a chemical modification called N1-methylpseudouridine are responsible for the ‘slips’ along the mRNA sequence.
In collaboration with researchers at the Universities of Kent, Liverpool and Oxford, the MRC Toxicology Unit team tested for evidence of the production of ‘off-target’ proteins in people who received the mRNA Pfizer vaccine against COVID-19.
The researchers found an unintended immune response occurred in one third of the 21 patients in the study who were vaccinated – but with no ill-effects, in keeping with the extensive safety data available on these COVID-19 vaccines.
They then redesigned mRNA sequences to avoid these ‘off-target’ effects, by correcting the error-prone genetic sequences in the synthetic mRNA, which produced the intended protein.
These design modifications can easily be applied to future mRNA vaccines to produce their desired effects while preventing hazardous and unintended immune responses.
Professor Anne Willis, Director of the MRC Toxicology Unit and joint senior author of the report, said: “These new therapeutics hold much promise for the treatment of a wide range of 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.
The researcher added: “Our work presents both a concern and a solution for this new type of medicine, and result from crucial collaborations between researchers from different disciplines and backgrounds.
“These findings can be implemented rapidly to prevent any future safety problems arising and ensure that new mRNA therapies are as safe and effective as the COVID-19 vaccines.”
Image: Mike Thornton, Still Vision Photography
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