Redesigning future mRNA therapeutics

MRC Toxicology Unit researchers have discovered that misreading of mRNAs therapeutics by the cell’s decoding machinery can cause an unintended immune response.

Messenger RNA (mRNA) therapeutics include the type of vaccine used to control the COVID-19 pandemic and are considered game-changing.

As well as being used to fight the COVID-19 pandemic, they are already proposed to treat various cancers, cardiovascular, respiratory and immunological diseases in the future.

The COVID-19 vaccines have extensive safety data and this study will contribute to the safety of new mRNA vaccines in the future.

Preventing unintended immune response

The unintended immune response in the body occurred in one third of those vaccinated, but with no ill-effects, in keeping with the extensive safety data available on these COVID-19 vaccines.

The researchers identified the sequence within the mRNA that caused this to occur and found a way to prevent ‘off-target’ immune responses to enable the safer design of future mRNA therapeutics.

mRNA is the genetic material that tells cells in the body how to make a specific protein.

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.

Revolutionary class of therapeutics

This revolutionary class of therapeutics was made possible in part through the work of biochemist Katalin Karikó and immunologist Drew Weissman.

They demonstrated that by adding chemical modifications to the bases (the building blocks of mRNA) the synthetic mRNAs could bypass some of our body’s immune defences. This allows a therapeutic to enter the cell and exert its effects.

This discovery led to their award of the Nobel Prize in Physiology and Medicine in 2023.

Latest developments

The latest developments are led by biochemist Professor Anne Willis and immunologist Dr James Thaventhiran from the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge.

Their research builds upon 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, which are currently contained in mRNA therapies, are responsible for the ‘slips’ along the mRNA sequence.

Working in collaboration

The MRC Toxicology Unit team worked in collaboration with researchers at the universities of Kent, Oxford and Liverpool.

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

The team then redesigned mRNA sequences to avoid these ‘off-target’ effects, by correcting the error-prone genetic sequences in the synthetic mRNA.

Such design modifications can easily be applied to future mRNA vaccines to produce their desired effects while preventing hazardous and unintended immune responses.

Reliable vaccines of the future

Dr James Thaventhiran from the MRC Toxicology Unit, joint senior author of the report 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.

Promise for wide range of diseases

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.

Dr Thaventhiran, who is also a practising clinician at Addenbrooke’s hospital, said:

We can remove the error-prone code from the mRNA in vaccines so the body will make the proteins we want for an immune response without inadvertently making other proteins as well.

The safety concern for future mRNA medicines is that mis-directed immunity has huge potential to be harmful, so off-target immune responses should always be avoided.

Addressing global health inequalities

Professor Willis 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.

Using synthetic mRNA for therapeutic purposes is attractive because it is cheap to produce, so can address substantial health inequalities across the globe by making these medicines more accessible.

New COVID-19 variant vaccine

Moreover, synthetic mRNAs can be changed rapidly, for example to create a new COVID-19 variant vaccine.

In the Moderna and Pfizer COVID-19 vaccines, synthetic mRNA is used to enable the body to make the spike protein from SARS-CoV-2.

The body recognises the viral proteins generated by mRNA vaccines as foreign and generates protective immunity.

This persists, and if the body is later exposed to the virus its immune cells can neutralise it before it can cause serious illness.

Positioning of the ribosome

The cell’s decoding machinery is called a ribosome. It ‘reads’ the genetic code of both natural and synthetic mRNAs to produce proteins.

The precise positioning of the ribosome on the mRNA is essential to make the right proteins because the ribosome ‘reads’ the mRNA sequence three bases at a time.

Those three bases determine what amino acid is added next into the protein chain. Therefore, even a tiny shift in the ribosome along the mRNA will massively distort the code and the resulting protein.

Preventing ‘off-target’ protein production

When the ribosome is confronted with a string of these modified bases called N1-methylpseudouridine in the mRNA, it slips around 10% of the time.

This causes the mRNA to be misread and unintended proteins to be produced, enough to trigger an immune response.

Removing these runs of N1-methylpseudouridine from the mRNAs prevents ‘off-target’ protein production.

This research was jointly funded by MRC and the Wellcome Leap RNA Readiness + Response programme.

Top image:  Credit: Dr_Microbe, iStock, Getty Images Plus via Getty Images

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