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mRNA mod responsible for off-target effects identified & fixed

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mRNA mod responsible for off-target effects identified & fixed

Researchers have discovered that a chemical modification to the synthetic messenger RNA used in therapeutics can cause the cell’s machinery to misread its instructions and result in unintended immune responses. Importantly, they’ve also discovered a solution to the problem.

Messenger RNA, mRNA, tells cells in the body how to make a specific protein. It’s also an effective way of combatting disease, exemplified by its use in vaccines for SARS-CoV-2 and personalized cancer vaccines. mRNA therapeutics came about when biochemist Katalin Karikó and immunologist Drew Weissman discovered that inserting subtle chemical modifications into the bases – the building blocks – of synthetic mRNAs could bypass some of the body’s immune defenses, allowing a therapeutic to enter a cell and exert its effects.

Now, research led by the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge has discovered that the cellular machinery that ‘reads’ mRNA can slip up when confronted with repeats of a particular chemical modification commonly found in mRNA therapeutics, leading to the production of ‘off-target’ proteins that can trigger an unintended immune response. And, importantly, they’ve devised a solution.

“The safety concern for future mRNA medicines is that misdirected immunity has huge potential to be harmful, so off-target immune responses should be avoided,” said James Thaventhiran, co-corresponding author of the study. “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 cell’s decoding machinery is called a ribosome, and it’s responsible for ‘reading’ the genetic code of natural and synthetic mRNAs to produce proteins. The precise positioning of the ribosome on the mRNA is essential to making the correct – that is, ‘on-target’ – proteins because it reads the mRNA three bases at a time to determine what protein is added to the chain next. So, even the smallest shift in the ribosome can massively distort the code and the protein produced.

The researchers, who’d collaborated with researchers at the Universities of Kent, Oxford and Liverpool, tested for evidence of the production of off-target proteins in people who’d received the Pfizer mRNA vaccine against SARS-CoV-2. In one-third of the 21 patients in the study, they found an unintended immune response – which produced no adverse effects – caused by the incorporation of N1-methylpseudouridine into the mRNA. The modified base had been introduced to increase the safety and efficacy of COVID-19 vaccines.

Ribosome confronted with a string of these modified bases was seen to ‘slip’ around 10% of the time, causing the mRNA to be misread and unintended proteins to be produced, which was enough to trigger an immune response. Removing the runs of N1-methylpseudouridine from the synthetic mRNA prevented the production of off-target proteins.

“Our work presents both a concern and a solution for this new type of medicine and results from crucial collaborations between researchers from different disciplines and backgrounds,” said Anne Willis, the study’s other corresponding author. “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.”

The study was published in the journal Nature.

Source: University of Cambridge

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