A breakthrough in mRNA research has been made at the UW

- With this technology, the medical world can think of much broader applications of mRNA. We are no longer just talking about the production of anti-covid vaccines, which seems to be the simplest application of mRNA technology. Such an efficiently translatable mRNA molecule can be used to design new anti-cancer therapies, apply to the treatment of rare diseases and various diseases with a genetic basis, says Prof. Jacek Jemielity of the University of Warsaw's Center for New Technologies (CeNT).

Work on a universal therapeutic mRNA

Researchers at the UW sought to modify the mRNA molecule in such a way as to obtain as much therapeutic protein as possible, with the lowest possible dose of therapeutic mRNA. In the present study, the researchers, inspired by biology, proposed a modification of the 5' end of the mRNA, in a position that often undergoes natural modifications under cellular conditions (methylation at the N6 position of adenosine as the first nucleotide at the 5' end). This is the so-called post-transcriptional modification, which occurs in cells already after mRNA biosynthesis. It is worth noting that this modification is reversible and there is an enzyme in cells capable of removing it (FTO). The function of this natural modification is not yet understood, but studies indicate that it is associated with increased mRNA productivity. Scientists replaced the methyl group with a much larger benzyl group. They found that it perfectly mimics the natural modification in terms of mRNA properties, but is not removable by the FTO enzyme. Thus, 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, for the production of which the instruction is written in such an mRNA molecule, is produced in much larger quantities.

- The modification we have introduced involves the attachment of a benzyl at a specific point at one end of the mRNA, the so-called cap. The benzyl is attached at a characteristic point where natural enzymes modify the mRNA by attaching 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 ourselves, studying how this would affect the properties of the mRNA," explains Dr. Marcin Warminski, first author on the paper.

The researchers gave the modification the name AvantCap. In the course of the study, the researchers proved that the mRNA molecule with AvantCap shows up to 6 times higher productivity in some systems. This means that the recipe for the production of a specific protein, contained in such a modified molecule, will result in the production of more than 6 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. Interestingly, under certain specific conditions, this difference can be even greater (up to 100 times). Scientists have tried to explain the mechanism behind the increased production of the protein in the cell due to the introduced modification, but the results of the research are not yet clear.

- 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 molecules a higher priority in translation. Such molecules are more efficiently decoded under certain conditions, leading to increased production of certain types of proteins. Our modification seems to produce just such a result - molecules get priority in the queue for protein production. Perhaps the mRNA becomes resistant to the action of some enzyme quenching 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 qualities," adds Joanna Kowalska, PhD.

mRNA more effective in living organisms than on plates

Importantly for the pharmaceutical community, the observed properties of the modified mRNA from AvantCap are more potent when administered to living organisms (mice) than in cell lines cultured in vitro. What's more, the researchers also proved that mRNA encoding a tumor-specific protein (known as antigen) given to tumor-bearing mice resulted in significant inhibition of tumor growth. Confirming this in the human body requires extremely expensive and lengthy clinical trials.

At the intersection of academia and industry

The discovery made is the result of several years of cooperation between academia and ExploRNA, a university spin-off company founded by Prof. Jacek Jemielite and colleagues. The professor stresses that without the cooperation of the academic and company teams, complementing each other's competencies, a discovery of this magnitude would not have been possible.

- Without a doubt, this was the most complicated and costly project of my scientific career. Personally for me, it is important to prove that scientific research does not have to be a compromise between utility and scientific quality. On the contrary, there is an excellent synergy in the cooperation between academia and the goals of a biotech company. On the one hand, by cooperating between the academy and the company, we can rise above the constraints we face as an academic team, creating even better science. On the other hand, by developing highly developed technologies derived directly from scientific research, the company gains a significant competitive advantage, and the results obtained will almost certainly find practical application and serve society. Admittedly, there is still a long way to go, requiring, among other things, a mature financing system for such activities, but I believe this will happen," says Prof. Jemielity.

The discovery has received patent protection and has been licensed by the UW to ExploRNA, which is developing the technology further and putting it into practice.

compiled based on press release