Nature: A new strategy to cure diseases one day and forever: Epigenetic silencing health and wellness

A team of Italian researchers has achieved a scientific milestone that heralds a revolution in the medical field. The authors have managed to silence genes associated with high cholesterol levels, without modifying DNA. Work on rats showed that the effects lasted for a full year of the experiment, a period equal to half of a human’s life. These results show that it is possible to solve chronic health problems in one day and forever. The study is published this Wednesday in the journal NatureRam of the best world science.

DNA is a book of 3,000 million chemical letters, containing instructions for the functioning of every cell. This vast text is divided into pages – genes – with specific recipes for making proteins essential to life: collagen in cartilage, hemoglobin in blood, antibodies that fight pathogens. One of these genes, PCSK9, contains guidelines for the production of proteins associated with high levels of bad cholesterol. The US company Verve Therapeutics announced on November 12 that it had edited the DNA of the liver cells of a dozen people with dangerous congenital hypercholesterolemia, disabling their genes. PCSK9 And managing to reduce cholesterol by half. This experimental therapy, called VERVE-101, was the first to use the revolutionary CRISPR gene editing tool to directly modify a patient’s DNA rather than cells in the laboratory.

The new study achieved something similar, but without making any changes to the DNA. The Italian team, led by biotechnologist Angelo Lombardo, did not make genetic changes, but rather epigenetic changes. If DNA is interpreted as words containing instructions, epigenetic modifications are like chemical utterances, with the ability to change the message. Lombardo’s group silenced this bad cholesterol gene by adding small molecules to the DNA of liver cells. “This is the first published demonstration that a single treatment with epigenetic editors can produce stable silencing of a gene,” say Italian scientists from the San Raffaele Telethon Institute of Gene Therapy in Milan.

Lombardo claims that “there are many diseases that can be treated with epigenetic editing.” The researcher mentions other liver pathologies, such as hepatitis B, caused by a virus that embeds its genetic material in a human cell. “In the context of cancer, we and other groups are using epigenetic editing to silence multiple genes in T lymphocytes (white blood cells that protect the human body), with the goal of training these cells to respond to tumors,” says Lombardo. We have to fight better.”

Italian biotechnologists and other American colleagues formed a company called Chroma Medicine in 2021 to “revolutionize the treatment of diseases” through epigenetic editing. The company, headquartered in Boston and Milan, was born with a financing of approximately 115 million euros. Among its co-founders is chemist David Liu, a Harvard University researcher who transformed medicine with his CRISPR genetic engineering tools such as base editors, a type of pencil with an eraser capable of removing a letter from DNA and replacing it. Have given. with other. The company Verve Therapeutics has used these sophisticated base editors to deactivate bad cholesterol genes in dozens of its first patients.

Angelo Lombardo defends that epigenetic editing has advantages over DNA modification. “It does not induce breaks in the genome, which can be toxic, and it can also be reversed with drugs or other epigenetic editing strategies that reactivate silenced genes. So you have potential antidotes in case of adverse effects,” he argues. The Italian biotechnologist emphasizes that this is an experimental therapy whose immense potential has not yet been confirmed in other animal tests, possibly in monkeys, but he believes that clinical trials in humans The tests “won’t take long.”

Epigenetics expert Manel Esteller praises the new work, in which he has not participated. What’s interesting about the case is that these changes seem to persist over time and are preserved even as the liver cells divide. The mechanisms of this persistence are not clear, but, if the study is validated in other animal models and transferred to humans, it could mean that it could treat the defect or overexpression of the gene with just a single dose. That would be enough to do,” analyzed Esteller, director of the Josep Carreras Leukemia Research Institute in the city of Badalona, ​​Barcelona. The scientists point out that, currently, there are nine epigenetic drugs approved for use in oncology, specifically in leukemia, lymphoma and soft tissue tumors. A month earlier, Esteller’s team discovered “factors that predict whether epigenetic treatment will be effective in a patient.”

spanish biologist jurde menendez caravia and his colleagues at the University of Texas Southwestern (USA) used David Liu’s genetic pencil in mice a year ago to make subtle changes in the sequence of genes linked to several common diseases in the body. Menéndez Carvea says that “epigenetic silencing is a fundamental and innovative idea,” but it will not be able to replace the precision of the genetic pencil in his experiment. “One aspect to consider is keeping quiet.” off targeti.e., unwanted repression of genes that are not PCSK9, Writers report silence off target The consequences of many genes are unknown. “Its effects on liver cells need to be explored more deeply,” the biologist cautions.

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