An experimental treatment based on Crispr, the genome-wide “cut-and-stitch” technique that earned scientists Emmanuelle Charpentier and Jennifer Doudna the Nobel Prize in Chemistry in 2020, has shown promise for reducing cholesterol in unresponsive patients to any other therapy. The news, certainly positive and encouraging, was recently presented at the annual meeting of the American Heart Association by scientists from Verve Therapeutics, the company that developed the treatment. However, it should be underlined that the clinical trial of the therapy was conducted on a group of only ten patients, and therefore many other studies will still be needed, which will have to involve larger samples, before being able to confirm its real safety and effectiveness.
Gene therapy in the form of gel for butterfly children approved in the USA by Anna Lisa Bonfranceshi 20 July 2023
How the treatment works
“It’s an almost science fiction therapy,” he told al New York Times Martha Gulati, president of the American Society for Preventive Cardiology who was not involved in the study. It works like this: patients received a single administration of liquid nanoparticles, lipids that contained within them a sort of “atelier” to modify a single gene in the liver, the organ responsible for the synthesis of cholesterol. This gene, called PCSK9, is known to be linked to the increase in levels of the so-called “bad cholesterol”, i.e. LDL: hence the idea of blocking it with an external modification. The lipid nanospheres enter the bloodstream, reach the liver cells and open there, releasing two molecules: the first “instructs” the DNA to manufacture a gene editing tool, the second “guides” this tool to reach PCSK9 . And then the miracle happens: the instrument deletes a “letter” of the gene and overwrites it with another, suppressing its activity.
The experimentation: results and side effects
The inventors of the therapy administered different doses of the drug to the patients recruited in the trial. These are the main results: in the three patients who had received the highest dose, cholesterol levels decreased by a percentage between 39% and 55% (falling within the values considered normal); the same patients complained of flu-like symptoms that lasted a few hours as side effects. Two patients suffered from more serious side effects, which however those responsible for evaluating the safety of the study (independent of the researchers who conducted it) said were attributable to serious pre-existing heart diseases, deciding to continue the trial. One patient died of cardiac arrest five weeks after the infusion, which autopsy traced to coronary artery blockage. Finally, another patient had a heart attack the day after the infusion: investigating his case it emerged that he had already been suffering from chest pain for a few days before, but had not informed the experimenters, which would have excluded him from recruitment.
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Enthusiasm, doubts and cautions
The scientific community greeted the news with mixed reactions. On the one hand there are the enthusiasts: “The fact that we have managed to show that a genome editing technique works efficiently in the livers of living patients is already a revolution in itself – he commented to Science Gerald Schwank, researcher at the University of Zurich, Switzerland, who deals with genetic engineering. And again: “Even for seasoned doctors like me,” he said, again at New York Times, Fyodor Urnow, researcher at the Innovative Genomics Institute in Berkeley, California – this is a day we will remember. It’s like we’ve crossed the Rubicon, in a good way. It’s not a small step. It’s a leap into uncharted territory.” On the other hand, however, there are also those who urge caution. The doubts are first of all linked to the actual safety and effectiveness of this specific treatment, a topic on which the extremely small sample of patients, as we have already highlighted, prevents us from formulating a definitive conclusion, but also, more generally, on the technique on which based: Crispr is in fact still too “young” to fully know its safety in the medium and long term. “The treatment worked,” he said Karol Watson – cardiologist at the University of California, Los Angeles – but, beyond the side effects observed immediately, many years will still have to pass before we know if it is actually safe”. The company plans to conduct a new, larger study and has already recruited 40 patients in New Zealand and the UK; the trial could however also be extended to the United States, following the green light from the American regulatory authorities which arrived after receiving data showing that the treatment does not modify the DNA of sperm and oocytes (in other words, that the modifications made are not inherited from offspring).