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High cholesterol, turn off the faulty gene without changing the DNA

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High cholesterol, turn off the faulty gene without changing the DNA

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.

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. 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 to the patient’s bedside. 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 anti-Covid vaccines, which were finally administered in mouse models.

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«We have effectively confirmed that in the experimental models treated, PCSK9 is turned off in a stable and long-term way» underlines Martino Alfredo Cappelluti, first author of the study.

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