Modern gene therapies raise hopes of combating many diseases until now considered terminal. Nowadays, however, the methods are expensive and carry a risk of severe complications. Modifications of ribonucleic acid mRNA introduced by scientists from the Faculty of Physics, University of Warsaw in collaboration with the Louisiana State University are blazing a trail for safer and more effective gene drugs. Clinical trials of the first new-generation anti-cancer vaccine, developed in Germany with the aid of the Polish invention, will begin already later this year.
Gene therapies may be useful for the effective treatment of many diseases, including the most malignant forms of cancer. Nowadays, such methods concentrate on changing DNA. Yet manipulating genome is a risky venture. For years, scientists from the Faculty of Physics, University of Warsaw (FUW) have been working on a safer solution: modifying messenger RNA. "In collaboration with the Louisiana State University, we have developed and patented methods for increasing mRNA stability and enhancing its productivity in the production of therapeutic proteins. We are providing biologists with a universal tool which could potentially allow to develop effective vaccines against any form of cancer," explains Jacek Jemielity, PhD (FUW). On March 16, FUW and LSU signed a contract with the German company BioNTech, granting the licence for the production of modified mRNA. Having obtained the licence, Ribological, a subsidiary of BioNTech developing RNA-based immunotherapeutics against cancer, will begin the first phase of clinical trials of the new-generation anti-cancer vaccine already this year.
Proteins perform most of the essential tasks that ensure the proper functioning of a cell. Information on protein structure is stored in the DNA contained in every cell nucleus. In order for the required protein to be produced on the basis of this data, an mRNA acid chain with a copy of the gene containing a given protein structure needs to be formed in a cell nucleus. The production of such mRNA is called transcription. The produced mRNA is transported through nucleus membrane to the cytoplasm, and it is only there, by the process of translation, that the protein can be finally synthesized.
The main focus of traditional medicine is on combating diseases by regulating protein activity in cells through pharmacological agents introduced from outside. Starting from the 1970s, there have been constant attempts to develop different therapies - gene therapies. Their interference in the transcription or translation is such that proteins with given therapeutic properties are produced directly in cells.
The lifetime of mRNA chains is short: it is usually a matter of hours, not infrequently of minutes. Therapeutic mRNA injected into the organism would be decomposed by enzymes before it could reach the cells and produce the life-saving protein. This is why the main focus of attention has until now been on the modifications of DNA. Yet the interference in the DNA buried in the recesses of a cell nucleus is difficult, expensive and dangerous. "Introduced for therapeutic purposes, a change is permanently recorded in the genome, and its consequences can be hard to predict. We may as well cure one disease and another one will develop. Therefore, already years ago, we turned our attention to mRNA, especially to what may be found at one of the ends of its chain," says Prof. Edward Darżynkiewicz (FUW).
For a chemist, mRNA is a long and monotonous polymer, containing some 2000 nucleosides - building blocks that come in four varieties only. An atypical structure, however, may be found at one of the ends of mRNA: a specific chemical compound, attached to the rest of the chain by means of a triphosphate bridge. This structure, called a cap, protects the mRNA chain from destructive enzymes. It is also recognized by the eIF4e protein, which initiates protein production in the cytoplasm.
It was due to their own chemical methods that the scientists from FUW have developed and investigated many artificial varieties of cap structure. Several groups of structures discovered in this manner have been submitted for a patent. Compounds in which an oxygen atom in the triphosphate bridge was substituted with a sulphur atom have proven to be particularly significant. "An average mRNA particle consists of eighty thousand atoms; we have changed only one. This slight modification has had some fascinating consequences," says Joanna Kowalska, PhD (FUW). Conducted by the group led by Prof. Roberta E. Rhoads (LSU), investigations of mRNA chains with a new endpoint have proven it is possible to achieve a threefold increase in the lifetime of mRNA in a cell and a fivefold increase in its productivity in protein production. Tests on mice, in turn, conducted in Mainz by the BioNTech company and the local university, have revealed that the mice's immune system response to the given protein was three times stronger than in the case of unmodified mRNA. "These are very exciting results. The improvement obtained by using the modified cap analogs as developed at the University of Warsaw might turn out to be the key for an efficacious RNA-based immunotherapy," states Ugur Sahin, CEO of BioNTech and Professor at the University Medical Center Mainz.
The invention of the Polish scientists is paving the way for using the translation mechanism occurring in the cytoplasm for medical purposes. The new-generation drugs will have many merits. The compound introduced into the organism does not have to penetrate the cell nucleus. The lack of interference in the genome eliminates the risk of mutation, and the limited lifetime of mRNA chains allows a physician to trigger a particular response of the organism only when necessary. What is more, the defense reaction of the organism to foreign mRNA is considerably more specific than in the case of DNA. "Our methods for modifying and developing cap structures work perfectly well in test tubes, which is essential for anyone setting his or her mind on the industrial production of drugs," observes Jacek Jemielity, PhD.
The licence for the use of the methods related to the modifications of mRNA endpoints has just been bought by the German company BioNTech from Mainz. Already this year, they intend to begin the first phase of the clinical trials of a new anti-cancer drug, in which the therapeutic sequences of nucleotides in the mRNA end with a cap modified according to the guidelines laid down by the Polish scientists. The drug will be injected into the lymph nodes. There it will reach the dendritic cells, where the key elements of our immune system, T lymphocytes, will be able to specialize in destroying a protein singled out by the scientists.