Its use in vaccines against COVID-19 has proven that it is a molecule with immense therapeutic potential. RNA is in the process of revolutionizing the treatment of genetic diseases, cancer, and even common pathologies.
Ribonucleic acid, or RNA, has been the subject of intense research since it was discovered to perform multiple functions in our cells.
It is estimated that there are 30 to 100 million RNA molecules in each of the 30 trillion cells in our body. And we now know that there are different families of RNAs, several of which perform important catalytic functions that were not suspected ten years ago. These discoveries have even led scientists to consider RNA as a molecule at the origin of the emergence of life.
The roles of messenger RNA (mRNA) and transfer RNA (tRNA) have long been known. During the synthesis of a protein, the DNA sequence that corresponds to it is first transcribed into mRNA. Then, tRNAs decipher the genetic information written in the mRNA and provide the amino acids necessary for the composition of the protein in the ribosome, which is the protein manufacturing factory in the cell.
The American-Canadian sydney Altman, co-winner of the Nobel Prize in Chemistry in 1989, who died last April, was the one who co-discovered the catalytic, that is to say enzymatic, functions of RNA. “It was a great discovery because it made us realize that RNA has great functional versatility in our cells. There is today a great excitement to understand what the different RNAs do in our cells”, underlines the Dr.r Éric Lécuyer, principal investigator of the RNA Biology Research Unit at the Montreal Clinical Research Institute (IRCM), who is setting up a center for innovation and RNA medicine.
RNA and diseases
Molecules essential to the proper functioning of cells, RNA can therefore be the source of disease. For example, some forty neurodegenerative diseases — including a hereditary form of amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1, or Steinert’s disease, particularly prevalent in Saguenay–Lac-Saint-Jean, where one in 475 people is affected, compared to one in 8000 in the world – are caused by abnormal repetitions of certain nucleotides (basic elements of DNA) in the genome. These amplified segments of DNA are transcribed into RNA, which “then form aggregates in cell nuclei. These aberrant and toxic RNAs for the cell act like molecular sponges which [absorbent] proteins important in the regulation, transport and processing of RNAs and disrupt their normal functions,” explains Dr.r Lecuyer.
Once DNA has been transcribed into RNA, this first, so-called primary version of RNA undergoes various chemical changes (a maturation process). These are carried out by a molecular machinery composed of proteins that bind to RNA, strip it of its non-coding parts, transform it into mRNA, and then transport it to particular compartments of the cell.
Added to this maturation process is the presence of a few thousand microRNAs which come to pair up with RNA molecules to lower their expression or downright degrade them. “Some of these small RNAs are thought to be involved in carcinogenesis,” says Dr.r Lecuyer.
Spinal muscular atrophy, a genetic neuromuscular disease that affects children and causes their death at an early age, is caused by a defect (due to a mutation) in the production of proteins that bind to RNA. However, the Americans Adrian Krainer and the Dr Frank Bennett, of the pharmaceutical Ionis, have succeeded in developing a treatment consisting of a small synthetic RNA, called antisense oligonucleotide, which, by binding to the RNA resulting from the transcription of the defective gene, modifies the process of its maturation such that the production of the binding protein increases.
RNA therapies
Of course we know the vaccines to mRNAs that allowed us to emerge of the COVID-19 pandemic. But RNA vaccines are also considered to treat people carrying a genetic mutation causing the synthesis of an abnormal protein, which will often be responsible for a disease. By injecting the mRNA corresponding to the normal protein, it would thus be possible to replace the defective one.
We understood that there are regions in the RNA sequence that will act as molecular postal codes to tell the cell where to transport this RNA, a bit like the postal code that we write on a letter that we put in the mail so that the postman delivers it to the right place
Initial attempts to use mRNA for vaccination against an infectious disease or as a curative protein replacement therapy have long failed because innate immunity induced the destruction of this mRNA, which it considered foreign, recalls the Dr Lecuyer. “We therefore modified certain nucleotides of this mRNA so that it appeared to be of endogenous source. These modifications improve the stability of the molecule, which is nevertheless degraded relatively quickly, and minimize the innate immune reaction. »
cancer vaccines
The strategy of an mRNA vaccine is also explored to fight cancer. This approach would, for example, make it possible to replace a tumor suppressor gene that would be absent or mutated in certain types of cancer. This mRNA could thus provide the proteins that block the proliferation of cancer cells.
Another possibility would consist in delivering to cancerous tumors an mRNA producing a protein capable of inducing apoptosis, ie programmed cell death. “If we were able to deliver this RNA directly into tumor cells, we would thus be able to selectively kill these abnormal cells, unlike therapeutic chemical agents (chemotherapy) which have a broad-spectrum effect leading to the death of all cells in the body having a proliferative mode of reproduction,” notes Dr.r Lecuyer.
“With a vaccine that we inject, we have a systemic effect that will be beneficial in preventing an infectious disease. But for cancer, the vaccine will have to have a more local effect. The big challenge is to develop approaches to deliver RNA molecules to the right tissues, to the right cells, and even to the right compartments of the cell, because therapeutic RNA often tends to end up in compartments that are not relevant, so that only a small proportion of these RNAs prove effective,” he explains.
Many researchers apply themselves to developing nanoparticles – to encapsulate RNA – to which they graft either antibodies which recognize markers on the surface of particular cells, or molecules which will have an affinity for a particular tissue. Nanoparticles are an important key to enabling delivery to the right tissue and cells, but once inside the cell, you have to find a way to reach the right compartment. The D teamr Lécuyer is working on this last step.
“We understood that there are regions in the RNA sequence that will act as molecular postal codes to tell the cell where to transport this RNA, a bit like the postal code that we write on a letter qu ‘we put in the post so that the postman delivers it to the right place. In my lab, we are trying to decipher these molecular postal codes that we would add to therapeutic RNA molecules in order to improve their delivery to the appropriate cellular compartment. We need to determine the postal code corresponding to each organelle in the cell,” explains Dr.r Lécuyer, whose team has developed genomic approaches combined with bioinformatics and machine learning to understand the nature of these RNA postal codes.
According to the researcher, RNA-based therapies are less risky than gene (DNA-based) therapies, which are more likely to leave traces in the patient’s genome. From an ethical point of view, it is more controversial to attempt to correct a mutation in a patient’s genome using CRISPR-Cas gene-editing technology or by the classic technique of administering viral vectors. in the hope that they will insert themselves at the place in the genome where the mutation is present, he believes.