Cambridge researchers redesign future mRNA therapeutics

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One-third of patients who received Pfizer’s COVID-19 vaccine had unintended immune responses

Researchers from the University of Cambridge’s Medical Research Council (MRC) Toxicology Unit have redesigned future messenger ribonucleic acid (mRNA) therapeutics to prevent potentially harmful immune responses.

mRNA is the genetic material that informs cells how to make a specific protein.

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.

Researchers found that the cellular machinery that ‘reads’ mRNAs ‘slip’ when confronted with repeats of a chemical modification commonly found in mRNA therapeutics, which lead to the production of off-target proteins that trigger unintended immune responses.

In collaboration with the Universities of Kent, Oxford and Liverpool, researchers investigated the prevention of any safety issues linked with future mRNA therapeutics.

The team tested for evidence of the production of off-target proteins in 21 people who had received Pfizer’s mRNA COVID-19 vaccine.

In one-third of the patients, researchers identified an unintended immune response with no-ill effects.

After re-designing mRNA sequences by correcting the error-prone genetic sequences in the synthetic mRNA, researchers produced the intended protein.

The decoding machinery in cells, known as the ribosome, reads the genetic code of both natural and synthetic mRNA to produce proteins.

When confronted with modified bases called N1-methypseudouridine in the mRNA, it slips around 10% of the time, causing the mRNA to be misread, producing unintended proteins and triggering an immune response.

When removing N1-methypseudouridine from mRNAs, off-target protein production can be prevented.

These modifications to mRNA therapeutics could be easily applied to future mRNA vaccines to produce strong effects while preventing unintended immune responses.

Additionally, synthetic mRNA for therapeutic purposes is cheap to produce, can address substantial health inequalities globally by making these medications more accessible and can be changed rapidly.

Professor Anne Willis, director, MRC Toxicology Unit, said: “These new therapeutics hold much promise for the treatment of a wide range of diseases” and should be “free from unintended side-effects”.

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