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New approach could produce modified mRNAs to treat a wide range of diseases

manhattantribune.com by manhattantribune.com
23 September 2024
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New approach could produce modified mRNAs to treat a wide range of diseases
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Multidimensional chemical screening of mRNA cap and 5’UTR modifications. Credit: Biotechnology of nature (2024). DOI: 10.1038/s41587-024-02393-y

The vital use of messenger RNA (mRNA) in COVID-19 vaccines has been a public example of the potential of mRNA-based therapies, which hold great promise for a wide range of therapeutic applications, from cancer immunotherapy to gene editing.

Working toward a systematic method for optimizing mRNA drugs for specific uses, researchers at the Broad Institute of MIT and Harvard and the Massachusetts Institute of Technology have developed an approach to tailor mRNAs to produce a greater abundance of proteins, or to produce proteins for a longer period of time, compared to native mRNA. This opens the door to delivering mRNA therapies at lower doses with fewer side effects for a variety of conditions.

Building on previous research that studied the attachment of multiple chemical “tails” to mRNA, the researchers, led by Broad Institute member Xiao Wang, systematically tested many different chemical modifications to mRNA and measured their effects on protein translation.

Building on what they learned from these experiments, they developed a framework, messenger RNA oligonucleotide assembly by ligation, or LEGO, that allows researchers to chemically alter the structure of mRNA molecules and influence their interactions with the cell’s protein translation machinery, thereby achieving the desired therapeutic effects. Their work on LEGO is published in Biotechnology of nature.

“The main goal of our project is to create therapeutics that harness the full potential of mRNA as an information molecule that can deliver any protein of interest,” said Hongyu Chen, a doctoral student in Wang’s lab and co-first author of the study with fellow doctoral students Dangliang Liu and Abhishek Aditham. “This is a very generalizable technology.”

The team ultimately hopes to create a comprehensive protocol that would allow researchers to optimize every component of an mRNA drug, achieving therapeutic control previously only possible in more traditional small molecule drugs.

“We ultimately want to synthetically extend the alphabet, create new structures, and decode the chemical language of mRNA medicine to maximize its potential in different therapeutic settings,” said Wang, who is the paper’s lead author and also the Thomas D. and Virginia Cabot Associate Professor of Chemistry at MIT.

Increased protein

The mRNA vaccines being developed for COVID-19 require only a modest amount of protein for the immune system to kick into action and develop robust antibodies against the infection. But in some diseases, such as hemophilia or diabetes, patients lack or have low levels of a protein, hormone or enzyme, and need therapies that can replace them in the body.

In their natural state, mRNA molecules have a short lifespan and are typically converted into proteins for only a short time before degrading. But depending on the therapeutic goal, an ideal mRNA treatment could produce proteins for a long time, reducing the number of times a patient would have to receive the treatment, or provide a large amount of protein quickly.

This is where LEGO could become incredibly beneficial.

LEGO allows researchers to optimize the efficiency of mRNA molecule translation by modifying their 5′ and 3′ ends (respectively their “caps” and “tails”). Modifying the cap of an mRNA can affect the quality of mRNA translation into proteins, while modifications to the tail impact the stability and degradation of the mRNA.

By mixing and matching cap and tail modifications, including adding multiple caps and tails branching off the molecule, Chen, Liu, Aditham, Wang and their colleagues found they could fine-tune the longevity and efficiency of mRNA translation to achieve specific therapeutic goals.

Researchers used LEGO to develop a hormone replacement therapy based on mRNA encoding the hormone erythropoietin, which stimulates red blood cell production to treat anemia. In mice, the drug — an mRNA with a double branch and other modifications — caused cells to produce eight times more protein than regular mRNA.

They also created an optimized COVID-19 vaccine, using the same mRNA modifications, which in mice triggered a 17-fold increase in antibody production compared to a conventional COVID-19 vaccine after two weeks.

In addition to optimizing the linear mRNA, the team also used LEGO to test modifications to circular mRNA, which is more resistant to degradation but which the cell translates using a less efficient method. By adding a branched cap to the circular RNA, the researchers created a “QRNA” that, when designed to encode a fluorescent protein, produces up to 60 times more fluorescence than regular circular RNA.

Although QRNA is far from becoming an effective therapeutic approach compared to linear mRNA, researchers were able to learn more about how cells naturally produce proteins by observing how different modifications affected the translation of QRNAs.

The results demonstrate the potential of mRNA to develop highly effective and targeted treatments for a wide range of pathologies while providing a framework for constructing mRNAs tailored to specific needs.

“In most of the applications we have already tested – in vaccines or in protein replacement therapies – we can achieve a much higher therapeutic effect with these modifications,” Liu said. “Such a tiny chemical change can contribute to an incredible increase in the stability and translatability of mRNA.”

More information:
Hongyu Chen et al., Chemical and topological design of multicapped mRNA and capped circular RNA to enhance translation, Biotechnology of nature (2024). DOI: 10.1038/s41587-024-02393-y

Provided by the Broad Institute of MIT and Harvard

Quote:New approach could produce modified mRNAs to treat a wide range of diseases (2024, September 23) retrieved September 23, 2024 from

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without written permission. The content is provided for informational purposes only.



Tags: approachdiseasesModifiedmRNAsproducerangetreatwide
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