by Health Editorial Staff
A study has been published in Nature which demonstrates the in vivo effectiveness of a treatment, to be carried out only once in a lifetime, on a gene responsible for familial hypercholesterolemia. It could also be used for other diseases
After genetic editing, i.e. the targeted modification of the DNA sequence of a gene, comes epigenetic editing: the possibility of modulating the level of activation of a gene without intervening on its sequence. It is an area of research that has become very active in recent years and now an article1 in the journal Nature offers the first proof of its long-term effectiveness in switching off a gene in vivo, in a model organism.
The work was signed by Angelo Lombardo’s team, head of the Epigenetic Regulation and Targeted Genome Modification laboratory at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan and professor at the Vita-Salute San University Raffaele (UniSR).
The “bad” gene
The gene in question is called PCSK9 and is involved in the regulation of cholesterol levels in the blood. Some mutated variants of this gene cause familial hypercholesterolemia: a rare genetic condition characterized by a high risk of serious cardio- and cerebro-vascular diseases, such as heart attack and stroke, even at a young age. «In some patients with the disease, the gene is more active than normal and this leads to a lower effectiveness of the liver cells in “capturing” the so-called “bad” cholesterol, LDL. The consequence is an increase in cholesterol levels in the blood, which in turn is responsible for the increase in cardiovascular risk”, explains Lombardo.
Some innovative therapies have already arrived in the clinic that aim to inactivate this gene in patients with familial hypercholesterolemia, including a gene editing platform that acts on the DNA sequence, and others are in an advanced phase of testing. For various reasons, however, PCSK9 also represents an excellent target for the newest epigenetic silencing technology.
What is epigenetics
To understand what it is, it is best to start from the concept of epigenetics: a set of mechanisms that regulates the state of expression of genes, i.e. whether they are turned on or off, without intervening on the DNA sequence. For example, it may involve the addition or elimination of particular chemical groups to the DNA molecule, such as to make it more or less accessible to the cellular machinery that initiates the process responsible for protein synthesis.
Epigenetic silencing therefore means the possibility of turning off the expression of a target gene by intervening precisely on these mechanisms.
«It is a sort of molecular switch that prevents the conversion of the information contained in the target gene into the corresponding protein» clarifies Lombardo, one of the world pioneers of this technology».
Experiments on mice
The approach immediately gave excellent results in in vitro experiments, in cell lines, but an in vivo test was still missing: a fundamental step in moving from the laboratory bench to the patient’s bed. And this is exactly the evidence obtained by Lombardo’s group for the PCSK9 gene.
First, the researchers developed molecules (called editors in jargon) programmed to recognize and switch off this gene, adding particular chemical groups to its sequence.
The second step was to encapsulate the editors in lipid nanoparticles, similar to those used for mRNA-based Covid vaccines, which were finally administered in mouse models. «We have effectively confirmed that in the treated experimental models PCSK9 is switched off in a stable and long-term way» underlines Martino Alfredo Cappelluti, first author of the study.
The prospects
This positive result now opens up various interesting perspectives, starting from the development of drugs based on epigenetic silencing for hypercholesterolemia, both familial and acquired, i.e. not caused by mutations in single genes and decidedly more common.
«Compared to other innovative treatments directed against PCSK9 – comments Lombardo -, this approach could have numerous advantages, as it is a therapy to be carried out only once in a lifetime, which does not modify the DNA sequence (with all the risks that this could entail ) and with potentially reversible effects. Furthermore, the demonstration of efficacy obtained constitutes a very solid basis for developing epigenetic silencing strategies directed again at the liver for other diseases, such as hepatitis B, but also at other organs, such as the central nervous system”.
Considering the interest of the SR-TIGET Institute in transferring the results of research to the patient, already in 2019, the Telethon Foundation and San Raffaele Hospital, together with professors Lombardo and Naldini, scientific creators, had founded a start-up, EpsilenBio, dedicated precisely to the development of an epigenetic silencing platform for the treatment of various diseases. The start-up was financed by Sofinnova-Telethon and acquired two years later by the American Chroma Medicine Inc. of Boston, one of the most important epigenetic silencing companies in the world, of which Professor Lombardo is co-founder.
February 28, 2024
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