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Researchers redesign future mRNA therapeutics to prevent potentially harmful immune responses

jg533 — Wed, 06 Dec 2023 16:02:31 +0000

mRNA - or ‘messenger ribonucleic acid’ - is the genetic material that tells cells in the body how to make a specific protein. Researchers from the Medical Research Council (MRC) Toxicology Unit have 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 are considered game-changing. They 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.

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 allowing 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, led by biochemist Professor Anne Willis and immunologist Dr James Thaventhiran from the MRC Toxicology Unit at the ̽��ֱ�� of Cambridge, build upon previous advances to ensure the prevention of any safety issues linked with future mRNA-based therapeutics. Their report was published on 6 December in the journal Nature.

̽��ֱ��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.

In collaboration with researchers at the Universities of Kent, Oxford and Liverpool, 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. They 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.

̽��ֱ��team then redesigned mRNA sequences to avoid these ‘off-target’ effects, by correcting the error-prone genetic sequences in the synthetic mRNA. This produced the intended protein. Such design modifications can easily be applied to future mRNA vaccines to produce their desired effects while preventing hazardous and unintended immune responses.

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

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 future safety of this medicine platform.”

“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,” said Professor Anne Willis, Director of the MRC Toxicology Unit and joint senior author of the report.

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. ̽��ֱ��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.”

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. 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. ̽��ֱ��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.

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

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 causing 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 funded by the Medical Research Council and the Wellcome LEAP R3 programme, and supported by the NIHR Cambridge BRC.

Reference: Mulroney, T E et al: ‘(N)1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting.’ Nature, Dec 23. DOI: 10.1038/s41586-023-06800-3

Researchers have discovered that misreading of therapeutic mRNAs by the cell’s decoding machinery can cause an unintended immune response in the body. They 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.

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.

Anne Willis

Libre de droit/ Getty Images

Strand of mRNA

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Canterbury suburbs were home to some of Britain’s earliest humans

ta385 — Wed, 22 Jun 2022 06:00:00 +0000

Archaeological discoveries made on the outskirts of Canterbury, England, confirm the presence of early humans in southern Britain between 560,000 and 620,000 years ago, making it one of the earliest known Palaeolithic sites in northern Europe.

Trophy hunting of lions can aid in conservation, but overhaul of system is required, say researchers

sc604 — Fri, 23 Sep 2016 07:00:00 +0000

One year after the worldwide controversy when an American dentist and recreational hunter killed Cecil the Lion outside Hwange National Park in Zimbabwe, the researchers say hunting can work as a conservation tool, but that an overhaul of the system is required in order to encourage hunting companies to prioritise sustainability over profits. Their findings are published in the journal PLOS ONE.

Although it may seem counterintuitive, most lion conservationists agree that trophy hunting can play a key role in conserving the species. Lions need large protected areas to thrive, but managing this land is expensive: in developing countries, the operating budgets for protected areas only cover an average of 30% of costs, and the fees raised from trophy hunting can cover some of this shortfall, making it financially feasible to protect lion habitat instead of developing it for other purposes. However, the researchers say the system is in need of reform if the species is to be protected in the long term.

̽��ֱ��researchers, from the Universities of Kent, Cambridge and Queensland, studied lion population trends between 1996 and 2008 in Tanzania’s Selous Game Reserve. Tanzania is home to up to half of the world’s free-ranging lions and is also the main location for lion trophy hunting in Africa.

̽��ֱ��game reserve, which is a stronghold for the species, is divided into blocks in which hunting rights are allocated to different companies. ̽��ֱ��government leases the land to the hunting companies, enforces hunting regulation and allocates the companies a species-specific annual quota per block.

̽��ֱ��researchers found that in areas where companies were allocated a particular block of land over a short time period (less than ten years), the numbers of lions killed, and the numbers of trophy species killed overall, were higher than the recommended numbers. In addition, annual financial returns were higher for these lands under short-term management.

In contrast, in blocks that were allocated to the same company for ten years or more, the number of offtakes, or licensed lion kills, were at level that were sustainable for the species, while also maintaining their habitat.

“Companies who have secured long-term use rights to natural resources are more likely to manage them sustainably,” said Dr Henry Brink from the ̽��ֱ�� of Kent, the study’s first author. “This is an important lesson for lion conservation, as loss of habitat means this species is increasingly restricted to protected areas.”

This research also supports calls to change the hunting fee system in Tanzania. “At present, the government sells hunting block fees cheaply, and raises more by setting high quotas and high fees for each trophy animal shot, which encourages those who are only allocated blocks over the short-term to shoot more lions, at the expense of long-term sustainability and profits,” said Professor Nigel Leader-Williams from Cambridge’s Department of Geography, the study’s senior author. “Increasing block fees, reducing trophy fees and reducing the hunting quota could bring in the same tax revenue, while reducing the temptation of hunters to kill more lions.”

Reference:
Henry Brink et al. ‘Sustainability and long term-tenure: lion trophy hunting in Tanzania.’ PLOS ONE (2016). DOI: 10.1371/journal.pone.0162610.

Adapted from a ̽��ֱ�� of Kent press release.

New research has found that controlled trophy hunting of lions can actually help conserve the species, but only in areas where hunting companies are given long-term land management rights.

Increasing block fees, reducing trophy fees and reducing the hunting quota could bring in the same tax revenue, while reducing the temptation of hunters to kill more lions.

Nigel Leader-Williams

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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