A molecule unknown to public opinion. Faced with DNA, the quintessential life molecule, RNA has always appeared as a younger brother. But now it seems to have taken a good revenge: thanks to the pandemic, it is now two years that the whole world has been talking about messenger RNA and vaccines which, exploiting the characteristics of this molecule, are today the most effective tools to fight the new coronavirus.
But the many forms of RNA promise to be far more revolutionary for medicine: the first drug that uses its characteristics, approved in 2014, paved the way for a bevy of new molecules and therapies. And the same companies that jumped to the headlines for anti Covid vaccines, are actually studying that same potential for dozens of diseases, from tumors to immunological diseases, from neurological to respiratory ones. And now all the laboratories in the world are working on RNA majesty, the molecule of wonders.
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Before the discovery
“For decades it was thought that the fundamental molecules for life were DNA and proteins, the first the custodian of information, the second the executors. But then, with the refinement of our biological knowledge, we realized that RNA played a very important role. important: it was as if at first we only saw the tip of the iceberg, “he explains Irene Bozzoni, full professor of Molecular Biology at the Sapienza University of Rome: “For example, we now know that the first form of life must have been a molecule of RNA and not of DNA because it has the two necessary characteristics: to reproduce while maintaining the set of information and to carry out specific functions “.
From the 1960s onwards, scientists have made discoveries about RNA and year after year its characteristics have appeared more and more interesting from a therapeutic point of view. On the other hand, it seems to be precisely in the number and complexity of the RNA molecules that the uniqueness of human beings resides, because their presence increases with the complexity of the organism. 20 years after the publication of the sequence of the human genome, it is now clear that what makes the difference between us and other species is certainly not the number of genes that code for proteins: we have about 25,000, a worm about 16,000. After all, not much less.
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“It was clear: there was something we didn’t see,” he explains Stefano Gustincich, director of the Central RNA Lab of the Italian Institute of Technology: «We have discovered that something in these two decades: another 35 thousand genes that are transcribed and not translated by non-coding RNAs. Science must now understand what they are for and study the enormous therapeutic potential of these non-coding RNAs “.
How many ANNs exist
In fact, there are many RNA, and each one has its own tasks. The most famous one encodes, that is, transfers genetic information, and is the messenger RNA: the molecule that is allowing us, with difficulty, to get out of the pandemic emergency. Vaccines that leverage its ability to encode Sars-CoV 2’s Spike protein have been the keystone in the fight against the novel coronavirus.
With the same technology, companies at the forefront of the development of Covid vaccines are developing solutions against other viruses, from Zika to cytomegalovirus, but also against cancers, first of all melanoma and lung cancer. With an approach that can also be personalized: Moderna is studying a way to create a vaccine that hits 20 specific targets expressed in each individual patient in a different way. BionTech is not far behind, and among the dozens of cancer vaccines being tested, it is studying customized solutions for solid tumors in an advanced or metastatic stage.
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Also in the oncology field, mRNA can be used to stimulate the production of molecules that activate the immune system against diseased cells. The versatility of this molecule also allows it to be used to improve cell therapies, that is, to modify the patient’s cells in the laboratory so that they produce specific proteins. Also in this case, melanoma is one of the diseases under study, with a system that combines cell therapy with immunotherapy, as well as some types of lymphomas.
But, as mentioned, this is just the tip of the iceberg. Then there are the non-coding ANNs. For example, those capable of activating and making some of the cells of the immune system, the T lymphocytes, work at their best, and to trigger them against cancer cells. The study that proves this was published in the past few weeks on Nature Genetics by an Italian team, led by Beatrice Bodegaprofessor of Molecular Biology, e Sergio Abrignaniprofessor of General Pathology, both of the University of Milan and of the National Institute of Molecular Genetics “Romeo and Enrica Invernizzi”.
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It is known, in fact, that the lymphocytes present in tumors are no longer able to eliminate tumor cells, but by silencing a specific type of RNA that accumulates in immature lymphocytes, the researchers made the so-called “guardian cells” acquire their ability to eliminate the sick ones. “We believe we have identified a potential new therapeutic target to combine with today’s immunotherapies with antibodies to checkpoint inhibitors,” explained the researchers, who are ready in the future to create a start-up that can develop new therapies based on their discovery.
On the other hand, for some years now, many RNAs have aroused interest and there are three types of molecule that really promise: the so-called “antisense oligonucleotides” (Aso), which are complementary to the coding molecules and are therefore used to modulate the production of proteins, the interfering RNAs, which prevent the translation of the instructions for the replication of genetic information, and the “RNA aptamers”, short molecules that bind to specific molecular targets, influencing their activity.
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And what are ASOs
Several Aso are already available today for therapeutic action such as nusinersen, used against spinal muscular atrophy, and inotersen, administered to patients suffering from hereditary amyloidosis due to transthyretin accumulation (hATTR), both approved by both the American Fda and from the European Ema; etlepirsen and golovirsen, for Duchenne’s dystrophy, which instead are approved only in the USA; and volanesorsen, approved in Europe, against familial chylomicronemia syndrome. All rare diseases that before these innovative drugs did not have valid therapies to rely on. Aso are also being studied for amyotrophic lateral sclerosis and Huntington’s disease, among other diseases, but the road still appears long.
There are also Sineups
Then there are long non-coding RNAs called Sineup that can be used to selectively increase the expression of a gene. “There are hundreds of diseases in which one of the two pairs of DNA does not work and therefore there is a halved production of proteins. Thanks to Sineups we can double the production of a protein starting from a single RNA”, explains Gustincich who founded Transine. Therapeutics, biotech that created a platform for the production of Sineup. A versatile technology that can be used in many fields, but which for now will focus on the production of molecules for the central nervous system and ophthalmology. A project that aroused interest, raising more than 9 million pounds of investment.
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How does the so-called “interference” of the ANNs work
Another mechanism exploited by some types of RNA is that of interference, which serves to block the expression of a gene. The first drug to exploit this ability was patisiran, indicated for polyneuropathy triggered by a rare disease, followed by givosiran, for hepatic porphyria, but many others are being studied.
Then there are the microRNAs, grains that can get stuck in the protein production mechanisms when they are defective. A versatile mechanism that is being studied for various pathologies, from tumors to infections. Finally, the aptamers which, although on paper they are very effective molecules, so much so that some think that in the future they can replace monoclonal antibodies, in practice have shown limitations. To date, only one is the approved drug that exploits its potential: pegaptanib, used for age-related macular degeneration.
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The molecule of wonders
In short, it’s been 15 years since The Economist he put RNA on the cover and suggested investments in this very field; who has done so now withdraws the dividend. To date, almost 20 drugs that act on the wonder molecule have already been approved and at least 500 are being studied. In Italy, the Italian Institute of Technology has been betting on RNA for years: “We started the program three years ago, today there are 22 research groups, which work with an interdisciplinary approach”, explains Gustincich. “We have brought together scientists who have worked all their lives on RNAs together with those who have never studied them but who are experts in the nervous system or in oncology. The goal is to position technology in biological processes. For this we also have scientists. computational that draw the RNAs that can have therapeutic and physical significance to imagine the nanoparticles capable of transporting the molecules “.
The “transport” problem
Here, transport appears to be the biggest obstacle to overcome today. “In the case of Duchenne’s dystrophy, for example, the problem is not the target, that is the defective gene, but the system with which we are able to transport and release the drug in the body. We know how to act with RNA but we have not yet found a fairly effective way to get to where it is needed, “explains Bozzoni, who is also one of the coordinators of the RNA working groups at the Italian Institute of Technology. And she adds: “The same is true for other diseases for which we have identified targets and modes of action but we still do not know how to ensure that the drug arrives intact where it is needed”.
Obviously there are many variables that must be evaluated – from the length of the molecule to be transported to the site where you want it to arrive – but when this problem is also addressed there will really be no limit to what can be done with the RNAs. “If we consider all the approved drugs we see that they insist on about 1000 proteins. This means that today we are able to interfere with the activity of 1% of the genome; if we want to hit the remaining 99% we have to use RNA”, he stresses. Gustincich.
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Essential technological investments
An enormous development potential that Italy will be able to seize as long as it is not found unprepared on the industrial front, as has already happened with Covid vaccines. “We must invest in technology transfer and develop the industrial chain. IIT together with the European Molecular Biology Laboratory of Monterotondo is working for this but we need the whole system”, concludes Gustincich. Only in this way will Italy also be able to enjoy the many potentials of His Majesty RNA.
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