mRNA, how messenger RNA drugs and vaccines will work

We are at the beginning of the 60s. Some researchers from King's College of Cambridge (UK) reveal a key secret for protein synthesis by the organism. In fact, there was a need to reveal what were the invisible characteristics of the “postman” who has the task of transposing the instructions carried in the DNA and being able to bring copies of small portions of the same DNA to the cellular ribosomes, the center of protein production. Well, this postman's name is Messenger RNA, or mRNA. It took decades to be able to use the skills of this cellular postman in medicine.

In the 1970s, researchers understood how to introduce it into cells, but only twenty years later did they begin to study the possibility of using it for preventive and therapeutic purposesthrough the development of mRNA vaccines.
But it is only with the two Nobel Prize winners in Medicine in 2023 Katalin Kariko and Drew Weissmann that we first came to hypothesize the role of mRNA and its possible use as a potential therapyeven going so far as to lay the foundations for the two vaccines created in a very short time for the prevention of infection by the Sars-CoV-2 virus, responsible for Covid.

I am currently thousands of studies on mRNA. As of 2023, there are just under 200 molecules in the phase of active experimental investigation or preclinical studies, a hundred in the clinical study phase, only 7 in the pre-registration phase and only 5 already approved, the vaccines for Covid -19. Meanwhile, the technology continues to develop, confirms its characteristics of great flexibility and proposes itself not only for the development of other vaccines but also as tool for making proteins available for therapeutic purposes. With future use in the treatment of rare pathologies and some forms of cancer, also thanks to the interaction of scientific studies with the opportunities offered by the use of Artificial Intelligence (AI).

What messenger RNA does and why it is essential

“In cells, messenger RNA plays a fundamental role in the synthesis of proteins: the genetic information contained in DNA is transcribed into messenger RNA, which, once released from the nucleus, binds to ribosomes, organelles located in the cell cytoplasm, and dictates the sequence of proteins to be produced“, explains Rita Carsetti, Immunologist at the Bambino Gesù Pediatric Hospital in Rome.

What happens in practice, in the invisible world of cells? Let's say that on the basis of the genetic characteristics of each individual, DNA behaves like the “mind”, that is, it decides what the cell needs, while l'mRNA carries information to the ribosomes which are activated to translate it into a specific protein. Be careful though. There is a characteristic of mRNA that should not be underestimated and it is the its very short duration of action.
“Messenger RNA as soon as it is used it is deleted and the cell is ready to receive other messages – continues the expert. The characteristics that make mRNA so useful in medicine are its ability to carry information and make our cells produce proteins and to represent a labile information system that does not persist and cannot modify the genome or the cell permanently.”

How an mRNA platform works

The use of mRNA for preventive and therapeutic purposes is based on the idea of ​​using synthetic messenger RNAs to transmit specific information within cells without modifying the DNA instructions. In practice, it involves transforming cells into “factories” of on-demand and extremely personalized vaccines or drugs, exploiting the information transmitted via messenger RNA synthesized in the laboratory. The possibility of design and production of vaccines and drugs in a short time, given the speed with which many microorganisms and malignant cells change. There mRNA technological platform responds perfectly to these needs.

“The mRNA technological platform presents some important advantages – reports Pier Luigi Lopalco, Full Professor of General and Applied Hygiene, Department of Biological and Environmental Sciences and Technologies, University of Salento. The first undoubted advantage, which we have been able to observe during the pandemic, is the speed of production. In January 2020, the genome of the SARS-CoV2 virus was isolated and the vaccine was produced after 7-8 months. Furthermore, the ability of mRNA technology to quickly adapt to changes in viruses susceptible to mutations such as influenza makes it an extremely flexible and versatile platform. Another non-secondary aspect concerns the phases of the production process, which takes place without the need to handle viruses, thus ensuring a high bio-safety; lastly, the logistical simplicity for the production of vaccines, which can even take place inside containers without the need for large laboratories”.

What is the difference between gene therapy and messenger RNA

Gene therapy refers to a technique that allows you to prevent or cure a disease thanks to the transfer of DNA. In the case of genetic diseases, it consists of introducing into the patient's body the functioning version of the gene that is defective or absent in that particular pathology. The transport of one or more copies of the therapeutic gene generally occurs thanks to gods viruses, appropriately modified so that they are harmless but still capable of doing what they normally do in nature: entering the host cell and transferring their genetic heritage there. Manipulated in this way, viruses become highly effective vectors for gene therapy. Obviously, in this sense, the availability of real “molecular scissors” that allow the “cut and sew” of genes must also be considered.
Through the Crispr technique DNA can be cut at specific points, thus deleting, replacing and literally rewriting entire sequences of the genetic code using the protein naturally present in a bacterium (called Cas9 endonuclease), which is guided by an RNA molecule. The mRNA technological platform will be able to express its maximum potential when combined with artificial intelligence (AI), which will enter all phases of planning, design and production of messenger RNA-based vaccines and drugs. Regulating the expression of the genome without modifying the genetic code is something that differs from classic gene therapy or the most innovative genome editing approaches, which act on the instructions that the organism contains in its DNA.

What will mRNA technology be useful for?

In general terms, there are four potential fields of action for the m-RNA platform:

  • preventive vaccines for infectious diseases
  • therapeutic cancer vaccines
  • drugs for rare genetic diseases
  • drugs for autoimmune diseases.

In the first case, the protein produced by the synthetic mRNA induces an antibody response from our immune system, but this concept is also applicable to tumors. Indeed, it can “train” the immune system to fight malignant cells which however mutate quickly. mRNA technology allows us to produce vaccines that target multiple antigens or to recognize a specific protein particularly expressed in a certain type of tumor. In this case, mRNA-based therapeutic vaccines are highly personalized (and combined with immunotherapy) on the individual patient and the type of tumor. But we don't stop at this point.

“Since mRNA is responsible for protein production, the technology can also be applied to all those rare genetic pathologies which are caused precisely by the lack of a specific protein due to a mutated gene. The mRNA produced in the laboratory can be prepared to reconstruct the production of that deficient protein, in this case the use of the viral vector is bypassed and the messenger RNA is supplied to the cell which becomes capable of reproducing the lost protein – underlines Mariangela Morlando , Associate Professor Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome”.

In short. The road is still long and there is no shortage of difficulties: first of all the instability of the mRNA, the efficiency with which it is translated into protein and how to encapsulate the RNA to be able to convey it to a specific cell type of the organism. But the prospects are encouraging because the results of the research could change the scenario of important diseases: Phase 2 clinical trials for vaccines in high-risk melanoma are currently underway; earlier-stage clinical trials for messenger RNA leading to the production of pro-inflammatory proteins for cancer; clinical trials for autoimmune diseases, for rare genetic diseases and a study involving data obtained during the clinical trial phase for a metabolic disease (propionic acidemia) in Phase 1 and 2.