Scientists from the University of Warsaw led by Prof. Jacek Jemielity and Prof. Joanna Kowalska, in cooperation with researchers from the Medical University of Warsaw and the UW spin-off company ExploRNA Therapeutics, have developed a new mRNA modification. The properties of the new molecule may be a breakthrough for modern medicine. Thanks to the discovery, it will be possible to further develop targeted therapies based on mRNA technology, including the treatment of rare diseases and the design of anticancer vaccines.

Messenger ribonucleic acid (mRNA) is the template for protein production in cells. It plays a key role in the expression of genetic information. Scientists from the University of Warsaw, together with researchers from other research units, have developed the new mRNA modification. Their research results were published in the Journal of the American Chemical Society (JACS).


“Thanks to this technology, the world of medicine can think about much broader applications of mRNA. We are no longer just speaking about the production of anti-Covid vaccines, which seem to be the simplest application of mRNA technology. The new mRNA molecule can be used to design anticancer therapies and be used in the treatment of rare diseases and various genetic diseases,” says Prof. Jacek Jemielity from the Center for New Technologies at the University of Warsaw, founder of the UW spin-off company ExploRNA Therapeutics, involved in the discovery of a new mRNA modification.


Therapeutic values

Researchers from the University of Warsaw were looking for a modification of the mRNA molecule that would allow obtaining as much therapeutic protein as possible with the lowest possible dose of therapeutic mRNA. In an article published in the JACS, they proposed modifying the 5′ end of mRNA in a position that is often subject to natural modifications in cellular conditions (methylation at the N6 position of adenosine as the first nucleotide at the 5′ end). It is the so-called post-transcriptional modification that occurs in cells after mRNA biosynthesis. Experts replaced the methyl group with a much larger one – benzyl.


This modification is reversible, there is an enzyme in the cells that can remove it (FTO). It turned out, however, that the mRNA modification not only perfectly imitates the natural modification, but it is also resistant to activity of the FTO enzyme. Thanks to this, the synthetic mRNA is somehow activated in terms of productivity, and the FTO enzyme is unable to turn off this activation. In practice, the desired protein is produced in much larger quantities.


“The change we introduced involves attaching benzyl at a specific point at one of the mRNA ends, the so-called Cap. Benzyl is attached at a characteristic site where natural enzymes modify mRNA by adding a methyl group to it after the mRNA has been synthesized. These natural mRNA modifications are reversible and can be removed. Inspired by biology, we decided to modify the mRNA in this position in a permanent way, examining how it would affect the properties of mRNA,” explains Dr Marcin Warmiński from the UW’s Faculty of Physics, the first author of the publication.


The scientists named the modification AvantCap. During the research, they proved that the mRNA molecule from AvantCap is up to six times more productive in some systems. It means that the recipe for the production of a specific protein contained in such a modified molecule will produce over six times more protein compared to mRNA using the technology used in anti-Covid vaccines. By administering such modified mRNA, it will be possible to achieve a therapeutic effect in the body at a much lower dose. Under certain specific conditions, this difference can be even greater (even a hundredfold).


“This is a very interesting phenomenon, but not yet fully explained. We know that certain natural modifications that occur after mRNA transcription in cells give the molecules a higher priority for translation. Such molecules are decoded more efficiently under certain conditions, leading to increased production of certain types of proteins. Our modification seems to give this result – the molecules gain priority in the queue for protein production. Perhaps mRNA becomes resistant to the action of some enzyme that quenches its extraordinary biological activity, but verifying this requires further research. The most important thing is that as a result of the modification, we have an mRNA molecule with very interesting therapeutic values,” adds Prof. Joanna Kowalska from the UW’s Faculty of Physics.


mRNA effectiveness

The observed properties of modified mRNA from AvantCap are stronger when administered to living organisms (mice) than in cell lines grown in vitro. This information is important for the pharmaceutical community. Researchers from the University of Warsaw also proved that mRNA encoding an antigen protein characteristic of tumors, administered to mice suffering from cancer, significantly inhibited tumour development. However, confirming this in the human body requires extremely expensive and long-term clinical trials.


The discovery is the result of several years of cooperation between the academic scientific group and ExploRNA – a university spin-off founded by Prof. Jacek Jemielity and colleagues. The discovery was patented and licensed by ExploRNA, which is responsible for further development of the technology and its implementation in practice.