With infectious diseases spreading rapidly, it’s become essential to respond faster and develop new vaccines quickly. Nevertheless, creating the mRNA used in these vaccines has challenges due to its two-fold production method, which includes both chemical synthesis and a slower enzyme-based process. A research group has introduced an advanced technology that enables the production of completely chemically synthesized mRNA with high purity, eliminating the need for enzymes altogether. This new approach allows for quicker and purer mRNA production, facilitating a faster response to viral outbreaks and new illnesses.
In today’s world, where viral outbreaks can turn into global pandemics in no time, the rapid development of new vaccines is critically important. Unfortunately, the vaccine production speed is limited because the mRNA involved is produced through a combination of chemical synthesis and enzyme-based synthesis, which takes longer.
A research team from Nagoya University in Japan has made a significant breakthrough by creating a novel synthesis technology for producing high-purity, fully chemically synthesized mRNA, thus eliminating the slower enzymatic processes. This development lays the groundwork for quicker responses to viral threats and new diseases, which could help manage future infections at an earlier stage. Their findings were shared in the journal Nucleic Acids Research.
Due to its crucial contribution to controlling the COVID-19 pandemic, mRNA is now increasingly recognized for its potential to fight infectious diseases. Experts believe that mRNA technology could also be instrumental in treating genetic disorders and emerging diseases in the future. However, the production of mRNA continues to be a challenge primarily because of concerns regarding purity and the speed of production.
Fully chemically synthesized mRNA can help overcome these hurdles. Masahito Inagaki noted: “One of the major benefits of fully chemically synthesized mRNA is that it avoids the intricate and slow enzymatic reactions that are usually part of mRNA production. A purely chemical approach would considerably shorten the production timeline.”
Additionally, this method is advantageous for individuals who have strong immune reactions to vaccines. mRNA sourced from 5′-monophosphorylated RNA can be prone to contamination by incomplete RNA fragments, triggering a robust immune response that may lead to side effects, especially inflammation. Yet, current purification methods have not been very effective at eliminating these impurities, which limits potential uses.
To tackle this issue, Professor Hiroshi Abe, doctoral student Mami Ototake, and Assistant Professor Inagaki developed a new phosphorylation reagent that contains a nitrobenzyl group, which functions as a hydrophobic purification tag.
Inagaki explained: “Because nitrobenzyl groups possess high hydrophobicity, when they are added to the RNA molecule, the mRNA becomes more hydrophobic. Impure RNA, on the other hand, does not have nitrobenzyl groups, allowing for easy separation from the target RNA via reverse-phase high-performance liquid chromatography. This method successfully produces pure RNA without the length variations and impurities common in transcription-based synthesis.”
The team did not stop at fully synthesizing mRNA; they also produced pure circular mRNA using the same technique. Circular mRNA is unique as it doesn’t have terminal structures, making it more durable against degradation by nucleic acid-cleaving enzymes in the body, thus providing a longer-lasting therapeutic effect.
This advancement in mRNA production could significantly impact future medical therapies. Abe mentioned, “This innovation signals a new era for highly efficient manufacturing of fully chemically synthesized mRNA and circular mRNA, both of which could transform RNA drug discovery and broaden the potential for mRNA-based treatments.”
Enhanced speed and purity in vaccine production could greatly improve our preparedness for future infectious disease threats. Looking ahead, the team is eager to apply these innovations to develop new mRNA vaccines targeting cancer antigens and genetic disorders.
