Thanks to a new technique, it was possible to 'turn off' the gene responsible for high cholesterol in mice without modifying the DNA sequence and also obtaining a long-lasting result: the effect remained active for about a year, that is, until the The experiment was not completed.
The result, published in the journal Nature, is entirely Italian: the study was led by the San Raffaele Telethon Institute for Gene Therapy in Milan, and the University of Eastern Piedmont, the Institute of Biomedical Technologies of the Council also participated National Research Institute of Segrate and the Vita-Salute San Raffaele University of Milan.
This is the first evidence of the long-term effectiveness of this technique and the strategy could also be useful for other diseases.
The researchers coordinated by Angelo Lombardo concentrated their efforts on the Pcsk9 gene, which is involved in the regulation of cholesterol levels in the blood.
Some variants of this gene, in fact, cause familial hypercholesterolemia, a rare genetic disease characterized by a high risk of heart attack and stroke even at a young age.
“In some patients with the disease, the gene is more active than normal – explains Lombardo – and this causes the liver cells to be unable to efficiently capture the so-called 'bad' cholesterol, or LDL: the consequence is an increase cholesterol levels."
There are already some therapies that aim to inactivate the gene by acting directly on the DNA sequence.
This type of approach shows some success, but there is also a fear that modifying DNA could lead to mutations or unwanted effects.
An equally promising alternative is therefore represented by the modification of the epigenome, that set of small molecules that attach to DNA and control the expression of genes without altering it.
The technique had never been tested in live animals and this is the main success achieved by the Italian experiment: a fundamental step in moving from the laboratory to the patient.
The authors of the study developed molecules programmed to recognize and switch off the Pcsk9 gene, and encapsulated them inside nanoparticles made of fats, similar to those also used for anti-Covid vaccines, which allow it to travel in the blood and reach the liver.
A single administration was sufficient to silence the gene in mice: “We have effectively confirmed that Pcsk9 is switched off in a stable and long-term way,” says Martino Alfredo Cappelluti, first author of the study.
This positive result now opens new perspectives, starting from the development of drugs based on epigenetic silencing for the treatment of hypercholesterolemia, both hereditary and acquired, which is much more common.
“Compared to other innovative treatments, this approach could have numerous advantages, since 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,” comments Lombardo.
“Furthermore, the demonstration of its effectiveness paves the way for therapies for other disorders involving the liver, such as hepatitis B, but also other organs, such as the central nervous system.”
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