A study published in Nature reports the results of research conducted by a team of scientists led by Ritu Thamman of Pennsylvania State University, who have managed to drastically reduce the level of LDL cholesterol in humans after injecting them with an experimental gene-editing treatment.

Cholesterol linked to low-density lipoproteins, known as LDL (Low-Density Lipoprotein) cholesterol, constitutes the atherogenic fraction of this fat that can cause deposits in the arteries that can trigger cardiovascular accidents such as myocardial or cerebral infarction.

The new gene editing therapy, which has been applied in humans for the first time, combats this fraction of cholesterol by manipulating DNA and permanently deactivates the PCSK9 gene, which is active in the liver and controls the level of low-density lipoprotein (LDL).

It has been developed by Verve Therapeutics, a biotechnology company based in Boston (Massachusetts, USA), which stated that a single injection of VERVE-101 reduced the amount of LDL in the blood by up to 55% in trial participants.

It is now known that one of the recruited volunteers died after participating in the trial, in which 9 other people participated. The 10 volunteers, who had high levels of LDL cholesterol since birth due to a congenital disease, received an injection of VERVE-101 to deactivate the aforementioned PCSK9 gene. After 28 days, the subjects saw their LDL cholesterol level reduced by up to 55%. Before the experiment, their plasma level was twice as high as usual.

Six months after injection, participants who received the highest dose of VERVE-101 continued with the 55% reduction in LDL, however, they suffered fever and headaches, flu-like symptoms, accompanied by a transient increase in liver enzyme levels, which returned to normal within days.

Most seriously, one of the 10 patients died of a heart attack five weeks after receiving VERVE-101, while a second participant had a heart attack one day after the injection. According to the authors of the study, a correlation between the administration of the treatment and heart attacks cannot be assured, since both volunteers suffered from advanced heart disease.

Bioethical assessment

The application of gene editing techniques in clinical practice constitutes a promising future for the correction of genetically based diseases, thanks to the new possibilities of CRISPR-Cas9 technology. Its use, both on adult and germ cells, would allow the suppression, modification or replacement of genes responsible for certain pathologies.

Its application is not yet possible either in the germ cells or in the early embryo due to the lack of security and experience in this type of manipulation, that would genetically affect all the cells of the individual, with the consequences that may arise in the case of the appearance of undesirable effects. But its application on somatic cells in adult individuals is already a reality. The recent results in the case of the treatment of a woman with sickle cell anemia demonstrate this, although the technique is not without risks.

As we have alredy published in our Observatory, after the complete sequencing of the human genome in 2022, as published in Science, the possibilities of intervening by manipulating this sequence for therapeutic purposes increased. Others of more dubious ethical acceptability, such as the introduction or suppression of certain characteristics of individuals, have also increased.

Reality has shown that the simple knowledge of the genomic sequence is not enough to go deeper into the way in which these genes interact with each other, so that modifications to some of them cause uncontrolled effects that are difficult to predict.

Researchers must be prudent to allow for a weighted evaluation of the risks and must sufficiently extend prior animal experimentation to avoid accidents in their use, given that it is a safety requirement in the application of these techniques in humans.

The use of safer therapeutic alternatives, if available, should be the first option until gene therapies have reached well-proven levels of safety and efficacy.

Julio Tudela and Cristina Castillo

Bioethics Observatory – Institute of Life Sciences

Catholic University of Valencia


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