Researchers Redesign the Future of mRNA Therapeutics

Scientists have unearthed that errors in the interpretation of therapeutic mRNA by the cell’s decoding apparatus can incite an inadvertent immune reaction within the body.

Messenger RNA or mRNA strand 3D rendering

Image Credit: MattL_Images/Shutterstock.com

They have pinpointed the specific mRNA sequence responsible for this phenomenon and devised a strategy to avert “off-target” immune responses, ensuring the safer formulation of forthcoming mRNA therapeutics.

mRNA, or “messenger ribonucleic acid,” serves as the genetic blueprint instructing cells on how to generate a particular protein. Researchers at the Medical Research Council (MRC) Toxicology Unit have revealed that the cellular machinery responsible for “reading” mRNAs encounters difficulties when faced with repetitions of a chemical modification commonly present in mRNA therapeutics.

These interruptions, in addition to the intended protein, result in the production of “off-target” proteins, triggering an unintended immune response.

mRNA vaccines, heralded as groundbreaking, have played a pivotal role in managing the COVID-19 pandemic and are poised for potential applications in treating various cancers, cardiovascular, respiratory, and immunological ailments.

This innovative therapeutic class owes its existence, in part, to the pioneering work of biochemist Katalin Karikó and immunologist Drew Weissman.

Their groundbreaking discovery, which earned them the Nobel Prize in Physiology and Medicine in 2023, demonstrated that by introducing chemical modifications to the bases of mRNA—the fundamental building blocks—synthetic mRNAs could bypass some of the body’s immune defenses, allowing therapeutics to enter cells and exert their effects.

The latest breakthroughs, spearheaded by biochemist Professor Anne Willis and Immunologist Dr. James Thaventhiran from the MRC Toxicology Unit at the University of Cambridge, build on previous advancements to ensure the preemptive mitigation of safety concerns associated with future mRNA-based therapeutics.

The study findings are published in the journal Nature.

The researchers identified that bases with a chemical modification known as N1-methylpseudouridine—currently present in mRNA therapies—are accountable for the “slips” along the mRNA sequence.

Collaborating with researchers from the Universities of Kent, Oxford, and Liverpool, the MRC Toxicology Unit team investigated the production of “off-target” proteins in individuals who received the mRNA Pfizer vaccine for COVID-19.

They observed an unintended immune response in one-third of the 21 vaccinated patients in the study, yet without any adverse effects, aligning with the extensive safety data available for these COVID-19 vaccines.

Subsequently, the team reconfigured mRNA sequences to circumvent these “off-target” effects by rectifying error-prone genetic sequences in synthetic mRNA, resulting in the desired protein production. Such design modifications can be readily implemented in future mRNA vaccines, ensuring their intended effects while preventing hazardous and unintended immune reactions.

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.

Dr. James Thaventhiran, Joint Senior Author, MRC Toxicology Unit, University of Cambridge

Thaventhiran 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 a practicing clinician at Addenbrooke’s hospital, stated, “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.”

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.

Anne Willis, Joint Senior Author, Professor and Director, MRC Toxicology Unit, University of Cambridge

Utilizing synthetic mRNA for therapeutic applications holds significant appeal due to its cost-effectiveness, offering the potential to address substantial health disparities globally by enhancing the accessibility of these medicines. Additionally, synthetic mRNAs can be swiftly modified, such as for the development of a new COVID-19 variant vaccine.

In the case of the Moderna and Pfizer COVID-19 vaccines, synthetic mRNA is employed to prompt the body to produce the spike protein from SARS-CoV-2.

The immune system recognizes the viral proteins generated by mRNA vaccines as foreign, leading to the development of protective immunity. This immunity endures, allowing the body’s immune cells to neutralize the virus upon subsequent exposure, preventing serious illness.

The cellular machinery responsible for decoding is termed a ribosome, reading the genetic code of both natural and synthetic mRNAs to synthesize proteins.

The precise positioning of the ribosome on the mRNA is crucial for accurate protein synthesis, as the ribosome reads the mRNA sequence in triplets, determining the addition of amino acids into the protein chain. Even a slight displacement of the ribosome along the mRNA can significantly distort the genetic code and the resulting protein.

When the ribosome encounters a series of modified bases known as N1-methylpseudouridine in the mRNA, it slips approximately 10% of the time, leading to a misreading of the mRNA and the production of unintended proteins.

The presence of these N1-methylpseudouridine sequences in the mRNA can be eliminated to prevent the “off-target” production of proteins.

Source:
Journal reference:

Mulroney, T. E., et al. (2023) N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting. Nature. doi.org/10.1038/s41586-023-06800-3.

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