Hypercholestérolémie : des chercheurs développent une stratégie pour désactiver un gène défectueux sans modifier l'ADN

After gene editing, that is, targeted modification of a gene's DNA sequence, comes epigenetic editing: the ability to modulate the level of activation of a gene without intervening in its sequence. It is an area of research that has become very active in recent years, and now the article "Durable and efficient gene silencing in vivo by hit-and-run epigenome editing" in the journal Nature proposes the first evidence of its long-term effectiveness in shutting down a gene in vivo, in a model organism. The work is signed by the team led by Angelo Lombardo, head of the Laboratory of Epigenetic Regulation and Targeted Genome Modification at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan and professor at the Vita-Salute San Raffaele University (UniSR).

The gene in question is called PCSK9 and is involved in the regulation of blood cholesterol levels. Some mutated variants of this gene cause familial hypercholesterolemia: a rare genetic condition characterized by high risk of serious cardio- and cerebrovascular 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, resulting in liver cells being less effective in “catching” so-called “bad” cholesterol, LDL. The consequence is a rise in blood cholesterol levels, which in turn is responsible for increased cardiovascular risk," Lombardo explains. A number of innovative therapies that aim to inactivate this gene in patients with familial hypercholesterolemia have already arrived in the clinic, including a gene editing platform that acts on DNA sequence, and others are in advanced stages of testing. For various reasons, however, PCSK9 also represents an excellent target for the newest epigenetic silencing technology.

To understand what this is about, it is convenient to start with the concept of epigenetics: a set of mechanisms that regulates the state of expression of genes, that is, whether they are turned on or off, without intervening in the DNA sequence. For example, it may be the addition or removal 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. Thus, epigenetic silencing refers to the ability to turn off the expression of a target gene by acting on precisely these mechanisms. "It is a kind 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.

The approach immediately yielded excellent results in in vitro experiments, in cell lines, but in vivo testing was still lacking a critical building block for moving from the lab bench to the patient bedside. This is exactly the evidence obtained by Lombardo's group for the PCSK9 gene. First, researchers developed molecules (called editors in the jargon) programmed to recognize and turn off this gene by adding particular chemical groups to its sequence. The second step was to encapsulate the publishers in lipid nanoparticles, similar to those used for mRNA-based anti-Covid vaccines, which were finally administered in mouse models. "We have indeed confirmed that in treated experimental models PCSK9 is turned off stably and in the long term," emphasizes Martino Alfredo Cappelluti, the first author of the study.

This positive result now opens up several interesting prospects, starting with the development of drugs based on epigenetic silencing for hypercholesterolemia, both familial and acquired, i.e. not caused by mutations in individual genes and definitely more common. "Compared with other, albeit innovative, treatments directed against PCSK9," Lombardo comments, "this approach could have numerous advantages, as it is a once-in-a-lifetime therapy that does not alter the DNA sequence (with all the risks this could entail) and has potentially reversible effects. Moreover, the demonstration of efficacy obtained provides a very solid basis for developing epigenetic silencing strategies again directed at the liver for other diseases, such as hepatitis B, but also at other organs, such as the central nervous system."

Considering the SR-TIGET Institute's interest in transferring research results to the patient, back in 2019, Fondazione Telethon and Ospedale San Raffaele, together with Professors Lombardo and Naldini, scientific originators, 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 funded by Sofinnova-Telethon and acquired two years later by Boston-based American Chroma Medicine Inc., one of the world's leading epigenetic silencing companies, of which Professor Lombardo is a co-founder.