Scientists from CNRS have developed new stable and effective messenger RNA (mRNA) sequences that enable cells to produce therapeutic proteins themselves, capable of inducing antibody production against certain viruses. Beyond mRNA vaccines, these patented advances open up possibilities for other therapies based on these molecules.
COVID-19 vaccines have made messenger RNA (mRNA) a star of biotechnology. These biomolecules carry instructions that enable cells to produce the protein arsenal they need. They are said to "code" for a given protein.
Illustration image Pixabay
Beyond naturally occurring mRNA in cells, biotechnology has developed artificial mRNA in recent years, which forces cellular machinery to produce other proteins, therapeutic ones for example. This is how the COVID-19 vaccine codes for the spike protein that enables the cell to defend itself against invasion by this virus.
But manufacturing an effective therapeutic mRNA is not so simple. First, a strategy must be found to administer this very fragile molecule into cells without it being instantly degraded in the body. CNRS scientists recently showed that
liposomes, small hollow capsules made of lipids, are a very versatile solution to achieve this. Then, once integrated into the cell, the mRNA must be correctly and efficiently "translated" into the desired protein.
Beyond the molecule sequence that carries the essential information to produce this protein, the so-called "untranslated regions" and the "poly(A) tail" of the mRNA must also be optimized - the terminal nucleotide sequence that ensures the stability and readability of mRNA in our cells. These invisible elements play a key role that is difficult to control and evaluate.
In this context, the team from the Molecular Biophysics Center in Orléans (CNRS) initiated a new study to test different combinations of untranslated sequences and introduced an innovation: a hybrid tail composed of two nucleotides, adenosine and guanosine (A/G tail). This version proves more stable during mRNA manufacturing steps than conventional tails composed exclusively of adenosine, without altering the ultimate protein production, whether in cultured cells or in mice. In other words, it represents a robust alternative to the tails used in current vaccines.
The scientists also screened several untranslated sequences, these regions located before and after the coding portion. Result: two new combinations prove particularly effective. These adjustments improve the quantity of proteins produced without modifying the overall stability of the mRNA.
To validate these discoveries, the team formulated mRNAs coding for the SARS-CoV-2 Spike protein in lipid nanoparticles, as in vaccines. When injected into mice, these optimized mRNAs trigger an immune response comparable to that obtained with the sequences used in the Pfizer-BioNTech vaccine.
These results, patented and published in the journal
Molecular Therapy Nucleic Acids, open perspectives beyond vaccines: they could also accelerate the development of therapeutic mRNAs against cancer, rare diseases, or for regenerative medicine. Another step toward a more stable and flexible "toolbox" of messenger RNA to meet tomorrow's medical challenges.