A team of Italian researchers has achieved a scientific milestone that will usher in a revolution in medicine. The authors managed to silence a gene linked to high cholesterol levels without having to change the DNA. The work carried out on mice shows that the effects lasted throughout the year the experiment lasted, a period equivalent to half a human life. These results suggest that it is possible to solve chronic health problems in a single day and forever. The study is published this Wednesday in the journal Nature, a source of the world's best science.
DNA is a book of 3 billion chemical letters and instructions for how every cell works. This huge text is divided into pages – the genes – with specific recipes for making the proteins essential to life: the collagen in cartilage, the hemoglobin in the blood, the antibodies that fight pathogens. One of these genes, PCSK9, contains the guidelines for the production of a protein linked to high levels of bad cholesterol. The American company Verve Therapeutics announced on November 12 that it had changed the DNA of the liver cells of a dozen people with dangerous congenital hypercholesterolemia, inactivated their PCSK9 gene and managed to reduce cholesterol levels by half. This experimental therapy, called VERVE-101, was the first to use the revolutionary CRISPR gene editing tools to alter DNA directly in a patient rather than in cells in the laboratory.
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The new study achieved something similar, but without changing the DNA. The Italian team led by biotechnologist Angelo Lombardo did not make genetic changes, but rather epigenetic ones. When DNA is interpreted as words with instructions, epigenetic modifications are like chemical accents 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. “It is the first published evidence that a single treatment with epigenetic editors can lead to stable silencing of a gene,” celebrates the Italian scientist from the San Raffaele Telethon Institute of Gene Therapy in Milan.
Lombardo proclaims that “there are many diseases that can be treated with epigenetic editing.” The researcher mentions other liver diseases such as hepatitis B, which are caused by a virus that embeds its genetic material into human cells. “In cancer, we and other groups use epigenetic editing to silence multiple genes in T lymphocytes.” [glóbulos blancos que defienden el cuerpo humano]with the aim of getting these cells to better fight tumors,” adds Lombardo.
The Italian biotechnologist and other American colleagues founded a company, Chroma Medicine, in 2021 to “revolutionize the treatment of disease” through epigenetic editing. The company, based in Boston and Milan, was founded with financing of around 115 million euros. Its co-founders include chemist David Liu, a Harvard University researcher who has transformed medicine with his CRISPR genetic engineering tools such as Base Editors, a type of pencil with an eraser capable of editing a single letter of DNA eliminate and replace with another. The company Verve Therapeutics used these advanced base editors to inactivate the bad cholesterol gene in its first dozen patients.
Angelo Lombardo argues that epigenetic editing has advantages over DNA modification. “It does not cause breaks in the genome, which can be toxic, and it can also be reversed with drugs or other epigenetic editing strategies that reactivate the silenced gene. “So in the event of side effects, you have possible antidotes,” he argues. The Italian biotechnologist emphasizes that it is an experimental therapy whose immense potential still needs to be confirmed in other animal studies, possibly on monkeys, but he believes that clinical trials on humans “will not take long”.
Epigenetics expert Manel Esteller praises the new work, in which he was not involved. “The strange thing about this case is that these changes appear to be maintained over time and even persist as liver cells divide.” “The mechanisms of this persistence are not clear, but the study is validated in other animal models and applied to humans “It could mean that it would be enough to simply treat a defect or excess of a gene with a dose,” analyzes Esteller , director of the Josep Carreras Leukemia Research Institute in the city of Badalona in Barcelona. The scientist explains that nine epigenetic drugs are currently approved for use in oncology, particularly in leukemia, lymphoma and soft tissue tumors. A month ago, Esteller's team discovered “the factors that predict whether or not an epigenetic treatment will be effective in a patient.”
The Spanish biologist Xurde Menendez Caravia and his colleagues at the University of Texas Southwestern (USA) used David Liu's gene pen in mice a year ago to make subtle changes in the sequence of a gene linked to a variety of common heart diseases. Menéndez Caravia explains that “epigenetic silencing is an original and novel idea,” but it could not have replaced the precision of the genetic pen in his experiment. “One aspect to consider is off-target silencing, i.e. the unwanted suppression of genes that are not PCSK9. The authors report silencing of several off-target genes, the consequences of which are unknown. What effects this would have on the liver cells would have to be researched in detail,” warns the biologist.
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